2,4-pyrimidinediamine compounds and their uses

ABSTRACT

The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 10/355,543filed Jan. 31, 2003, now pending, which claims benefit under 35 U.S.C. §119(e) to application Ser. No. 60/353,333 filed Feb. 1, 2002;application Ser. No. 60/353,267 filed Feb. 1, 2002; application Ser. No.60/399,673 filed Jul. 29, 2002; and application Ser. No. 60/434,277filed Dec. 17, 2002. The contents of application Ser. No. 10/355,543 areincorporated herein by reference.

2. FIELD OF THE INVENTION

The present invention relates generally to 2,4-pyrimidinediaminecompounds, pharmaceutical compositions comprising the compounds,intermediates and synthetic methods of making the compounds and methodsof using the compounds and compositions in a variety of contexts.

3. BACKGROUND OF THE INVENTION

Crosslinking of Fc receptors, such as the high affinity receptor for IgE(FcεRI) and/or the high affinity receptor for IgG (FcγRI) activates asignaling cascade in mast, basophil and other immune cells that resultsin the release of chemical mediators responsible for numerous adverseevents. For example, such crosslinking leads to the release of preformedmediators of Type I (immediate) anaphylactic hypersensitivity reactions,such as histamine, from storage sites in granules via degranulation. Italso leads to the synthesis and release of other mediators, includingleukotrienes, prostaglandins and platelet-activating factors (PAFs),that play important roles in inflammatory reactions. Additionalmediators that are synthesized and released upon crosslinking Fcreceptors include cytokines and nitric oxide.

The signaling cascade(s) activated by crosslinking Fc receptors such asFcεRI and/or FcγRI comprises an array of cellular proteins. Among themost important intracellular signal propagators are the tyrosinekinases. And, an important tyrosine kinase involved in the signaltransduction pathways associated with crosslinking the FcεRI and/orFcγRI receptors, as well as other signal transduction cascades, is Sykkinase (see Valent et al., 2002, Intl. J. Hematol. 75(4):257-362 forreview).

As the mediators released as a result of FcεRI and FcγRI receptorcross-linking are responsible for, or play important roles in, themanifestation of numerous adverse events, the availability of compoundscapable of inhibiting the signaling cascade(s) responsible for theirrelease would be highly desireable. Moreover, owing to the critical rolethat Syk kinase plays these and other receptor signaling cascade(s), theavailability of compounds capable of inhibiting Syk kinase would also behighly desirable.

4. SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel2,4-pyrimidinediamine compounds that, as will be discussed in moredetail below, have myriad biological activities. The compounds generallycomprise a 2,4-pyrimidinediamine “core” having the following structureand numbering convention:

The compounds of the invention are substituted at the C2 nitrogen (N2)to form a secondary amine and are optionally further substituted at oneor more of the following positions: the C4 nitrogen (N4), the C5position and/or the C6 position. When substituted at N4, the substituentforms a secondary amine. The substituent at N2, as well as the optionalsubstituents at the other positions, may range broadly in character andphysico-chemical properties. For example, the substituent(s) may be abranched, straight-chained or cyclic alkyl, a branched, straight-chainedor cyclic heteroalkyl, a mono- or polycyclic aryl a mono- or polycyclicheteroaryl or combinations of these groups. These substituent groups maybe further substituted, as will be described in more detail below.

The N2 and/or N4 substituents may be attached directly to theirrespective nitrogen atoms, or they may be spaced away from theirrespective nitrogen atoms via linkers, which may be the same ordifferent. The nature of the linkers can vary widely, and can includevirtually any combination of atoms or groups useful for spacing onemolecular moiety from another. For example, the linker may be an acyclichydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such asmethano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno,but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclichydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like),a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., —O—, —S—,—S—O—, —NH—, —PH—, —C(O)—, —C(O)NH—, —S(O)—, —S(O)₂—, —S(O)NH—,—S(O)₂NH—, —O—CH₂—, —CH₂—O—CH₂—, —O—CH═CH—CH₂—, and the like), amonocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino,thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and thelike) or combinations of such bridges.

The substituents at the N2, N4, C5 and/or C6 positions, as well as theoptional linkers, may be further substituted with one or more of thesame or different substituent groups. The nature of these substituentgroups may vary broadly. Non-limiting examples of suitable substituentgroups include branched, straight-chain or cyclic alkyls, mono- orpolycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono-or polycyclic heteroaryls, halos, branched, straight-chain or cyclichaloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclicalkoxys, branched, straight-chain or cyclic haloalkoxys,trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclicheteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls(thiols), imines, azos, azides, amines (primary, secondary andtertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates(any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonicacids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones,carboxylic acids, esters, amides, amidines, formadines, amino acids,acetylenes, carbamates, lactones, lactams, glucosides, gluconurides,sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamicesters, etc., and combinations of these groups. Substituent groupsbearing reactive functionalities may be protected or unprotected, as iswell-known in the art.

In one illustrative embodiment, the 2,4-pyrimidinediamine compounds ofthe invention are compounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3) haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN, —SCN, —NO,—NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d), —S(O)NR^(c)R^(c);—S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d), —OS(O)₂R^(d),—OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d), —SC(O)R^(d),—OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c), —SC(O)NR^(c)R^(c),—OC(H)NR^(c)R^(c), —SC(NH)NR^(c)R^(c), —[NHC(O)]_(n)R^(d),—[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R^(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR^(d),—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(NR^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently a protecting group or R^(a), or,alternatively, each R^(c) is taken together with the nitrogen atom towhich it is bonded to form a 5 to 8-membered cycloheteroalkyl orheteroaryl which may optionally include one or more of the same ordifferent additional heteroatoms and which may optionally be substitutedwith one or more of the same or different R^(a) or suitable R^(b)groups;

each R^(d) is independently a protecting group or R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In another aspect, the present invention provides prodrugs of the2,4-pyrimidinediamine compounds. Such prodrugs may be active in theirprodrug form, or may be inactive until converted under physiological orother conditions of use to an active drug form. In the prodrugs of theinvention, one or more functional groups of the 2,4-pyrimidinediaminecompounds are included in promoieties that cleave from the moleculeunder the conditions of use, typically by way of hydrolysis, enzymaticcleavage or some other cleavage mechanism, to yield the functionalgroups. For example, primary or secondary amino groups may be includedin an amide promoiety that cleaves under conditions of use to generatethe primary or secondary amino group. Thus, the prodrugs of theinvention include special types of protecting groups, termed“progroups,” masking one or more functional groups of the2,4-pyrimidinediamine compounds that cleave under the conditions of useto yield an active 2,4-pyrimidinediamine drug compound. Functionalgroups within the 2,4-pyrimidinediamine compounds that may be maskedwith progroups for inclusion in a promoiety include, but are not limitedto, amines (primary and secondary), hydroxyls, sulfanyls (thiols),carboxyls, carbonyls, phenols, catechols, diols, alkynes, phosphates,etc. Myriad progroups suitable for masking such functional groups toyield promoieties that are cleavable under the desired conditions of useare known in the art. All of these progroups, alone or in combinations,may be included in the prodrugs of the invention. Specific examples ofpromoieties that yield primary or secondary amine groups that can beincluded in the prodrugs of the invention include, but are not limitedto amides, carbamates, imines, ureas, phosphenyls, phosphoryls andsulfenyls. Specific examples of promoieties that yield sulfanyl groupsthat can be included in the prodrugs of the invention include, but arenot limited to, thioethers, for example S-methyl derivatives (monothio,dithio, oxythio, aminothio acetals), silyl thioethers, thioesters,thiocarbonates, thiocarbamates, asymmetrical disulfides, etc. Specificexamples of promoieties that cleave to yield hydroxyl groups that can beincluded in the prodrugs of the invention include, but are not limitedto, sulfonates, esters and carbonates. Specific examples of promoietiesthat yield carboxyl groups that can be included in the prodrugs of theinvention included, but are not limited to, esters (including silylesters, oxamic acid esters and thioesters), amides and hydrazides.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which the protectinggroup of R^(c) and R^(d) is a progroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (I) with substituentsadversely affects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I); and

R^(2b) and R^(4b) are each, independently of one another, a progroup.

In another aspect, the present invention provides compositionscomprising one or more compounds and/or prodrugs of the invention and anappropriate carrier, excipient or diluent. The exact nature of thecarrier, excipient or diluent will depend upon the desired use for thecomposition, and may range from being suitable or acceptable forveterinary uses to being suitable or acceptable for human use.

In still another aspect, the present invention provides intermediatesuseful for synthesizing the 2,4-pyrimidinediamine compounds and prodrugsof the invention. In one embodiment, the intermediates are4-pyrimidineamines according to structural formula (III):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I); LGis a leaving group such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I); and R^(4c) is hydrogen or a progroup.

In another embodiment, the intermediates are 2-pyrimidineaminesaccording to structural formula (IV):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I); LGis a leaving group, such as, for example, —S(O)₂Me, —SMe or halo (e.g.,F, Cl, Br, I) and R^(2c) is hydrogen or a progroup.

In yet another embodiment, the intermediates are 4-amino- or4-hydroxy-2-pyrimidineamines according to structural formula (V):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁵, R⁶ and L¹ are as previously defined for structural formula (I), R⁷is an amino or hydroxyl group and R^(2c) is hydrogen or a progroup.

In another embodiment, the intermediates are N4-substituted cytosinesaccording to structural formula (VI):

including salts, hydrates, solvates and N-oxides thereof, wherein R⁴,R⁵, R⁶ and L² are as previously defined for structural formula (I) andR^(4c) is hydrogen or a progroup.

In yet another aspect, the present invention provides methods ofsynthesizing the 2,4-pyrimidinediamine compounds and prodrugs of theinvention. In one embodiment, the method involves reacting a4-pyrimidineamine according to structural formula (III) with an amine ofthe formula HR^(2c)N-L¹-R², where L¹, R² and R^(2c) are as previouslydefined for structural formula (IV) to yield a 2,4-pyrimidinediamineaccording to structural formula (I) or a prodrug according to structuralformula (II).

In another embodiment, the method involves reacting a 2-pyrimidineamineaccording to structural formula (IV) with an amine of the formulaR⁴-L²-NHR^(4c) where L⁴, R⁴ and R^(4c) are as previously defined forstructural formula (III) to yield a 2,4-pyrimidinediamine according tostructural formula (I) or a prodrug according to structural formula(II).

In yet another embodiment, the method involves reacting a4-amino-2-pyrimidineamine according to structural formula (V) (in whichR⁷ is an amino group) with an amine of the formula R⁴-L²-NHR^(4c), whereL², R⁴ and R^(4c) are as defined for structural formula (III), to yielda 2,4-pyrimidinediamine according to structural formula (I) or a prodrugaccording to structural formula (II). Alternatively, the4-amino-2-pyrimidineamine may be reacted with a compound of the formulaR⁴-L²-LG, where R⁴ and L² are as previously defined for structuralformula (I) and LG is a leaving group.

In still another embodiment, the method involves halogenating a4-hydroxy-2-pyrimidineamine according to structural formula (V) (R⁷ is ahydroxyl group) to yield a 2-pyrimidineamine according to structuralformula (IV) and reacting this pyrimidineamine with an appropriateamine, as described above.

In yet another embodiment, the method involves halogenating anN4-substituted cytosine according to structural formula (VI) to yield a4-pyrimidineamine according to structural formula (III) and reactingthis pyrimidineamine with an appropriate amine, as described above.

The 2,4-pyrimidinediamine compounds of the invention are potentinhibitors of degranulation of immune cells, such as mast, basophil,neutrophil and/or eosinophil cells. Thus, in still another aspect, thepresent invention provides methods of regulating, and in particularinhibiting, degranulation of such cells. The method generally involvescontacting a cell that degranulates with an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to regulate or inhibit degranulation of the cell. The methodmay be practiced in in vitro contexts or in in vivo contexts as atherapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by or associated with cellular degranulation.

While not intending to be bound by any theory of operation, biochemicaldata confirm that the 2,4-pyrimidinediamine compounds exert theirdegranulation inhibitory effect, at least in part, by blocking orinhibiting the signal transduction cascade(s) initiated by crosslinkingof the high affinity Fc receptors for IgE (“FcεRI”) and/or IgG(“FcγRI”). Indeed, the 2,4-pyrimidinediamine compounds are potentinhibitors of both FcεRI-mediated and FcγRI-mediated degranulation. As aconsequence, the 2,4-pyrimidine compounds may be used to inhibit theseFc receptor signalling cascades in any cell type expressing such FcεRIand/or FcγRI receptors including but not limited to macrophages, mast,basophil, neutrophil and/or eosinophil cells.

The methods also permit the regulation of, and in particular theinhibition of, downstream processes that result as a consequence ofactivating such Fc receptor signaling cascade(s). Such downstreamprocesses include, but are not limited to, FcεRI-mediated and/orFcγRI-mediated degranulation, cytokine production and/or the productionand/or release of lipid mediators such as leukotrienes andprostaglandins. The method generally involves contacting a cellexpressing an Fc receptor, such as one of the cell types discussedabove, with an amount of a 2,4-pyrimidinediamine compound or prodrug ofthe invention, or an acceptable salt, hydrate, solvent, N-oxide and/orcomposition thereof, effective to regulate or inhibit the Fc receptorsignaling cascade and/or a downstream process effected by the activationof this signaling cascade. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with the Fc receptor signaling cascade, such as diseaseseffected by the release of granule specific chemical mediators upondegranulation, the release and/or synthesis of cytokines and/or therelease and/or synthesis of lipid mediators such as leukotrienes andprostaglandins.

In yet another aspect, the present invention provides methods oftreating and/or preventing diseases characterized by, caused by orassociated with the release of chemical mediators as a consequence ofactivating Fc receptor signaling cascades, such as FcεRI and/orFcγRI-signaling cascades. The methods may be practiced in animals inveterinary contexts or in humans. The methods generally involveadministering to an animal subject or human an amount of a2,4-pyrimidinediamine compound or prodrug of the invention, or anacceptable salt, hydrate, solvate, N-oxide and/or composition thereof,effective to treat or prevent the disease. As discussed previously,activation of the FcεRI or FcγRI receptor signaling cascade in certainimmune cells leads to the release and/or synthesis of a variety ofchemical substances that are pharmacological mediators of a wide varietyof diseases. Any of these diseases may be treated or prevented accordingto the methods of the invention.

For example, in mast cells and basophil cells, activation of the FcεRIor FcγRI signaling cascade leads to the immediate (i.e., within 1-3 min.of receptor activation) release of preformed mediators of atopic and/orType I hypersensitivity reactions (e.g., histamine, proteases such astryptase, etc.) via the degranulation process. Such atopic or Type Ihypersensitivity reactions include, but are not limited to, anaphylacticreactions to environmental and other allergens (e.g., pollens, insectand/or animal venoms, foods, drugs, contrast dyes, etc.), anaphylactoidreactions, hay fever, allergic conjunctivitis, allergic rhinitis,allergic asthma, atopic dermatitis, eczema, urticaria, mucosaldisorders, tissue disorders and certain gastrointestinal disorders.

The immediate release of the preformed mediators via degranulation isfollowed by the release and/or synthesis of a variety of other chemicalmediators, including, among other things, platelet activating factor(PAF), prostaglandins and leukotrienes (e.g., LTC4) and the de novosynthesis and release of cytokines such as TNFα, IL-4, IL-5, IL-6,IL-13, etc. The first of these two processes occurs approximately 3-30min. following receptor activation; the latter approximately 30 min.-7hrs. following receptor activation. These “late stage” mediators arethought to be in part responsible for the chronic symptoms of theabove-listed atopic and Type I hypersensitivity reactions, and inaddition are chemical mediators of inflammation and inflammatorydiseases (e.g., osteoarthritis, inflammatory bowel disease, ulcerativecolitis, Crohn's disease, idiopathic inflammatory bowel disease,irritable bowel syndrome, spastic colon, etc.), low grade scarring(e.g., scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), and sicca complex or syndrome. All of thesediseases may be treated or prevented according to the methods of theinvention.

Additional diseases which can be treated or prevented according to themethods of the invention include diseases associated with basophil celland/or mast cell pathology. Examples of such diseases include, but arenot limited to, diseases of the skin such as scleroderma, cardiacdiseases such as post myocardial infarction, pulmonary diseases such aspulmonary muscle changes or remodeling and chronic obstructive pulmonarydisease (COPD) and diseases of the gut such as inflammatory bowelsyndrome (spastic colon).

The 2,4-pyrimidinediamine compounds of the invention are also potentinhibitors of the tyrosine kinase Syk kinase. Thus, in still anotheraspect, the present invention provides methods of regulating, and inparticular inhibiting, Syk kinase activity. The method generallyinvolves contacting a Syk kinase or a cell comprising a Syk kinase withan amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit Syk kinaseactivity. In one embodiment, the Syk kinase is an isolated orrecombinant Syk kinase. In another embodiment, the Syk kinase is anendogenous or recombinant Syk kinase expressed by a cell, for example amast cell or a basophil cell. The method may be practiced in in vitrocontexts or in in vivo contexts as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by orassociated with Syk kinase activity.

While not intending to be bound by any particular theory of operation,it is believed that the 2,4-pyrimdinediamine compounds of the inventioninhibit cellular degranulation and/or the release of other chemicalmediators primarily by inhibiting Syk kinase that gets activated throughthe gamma chain homodimer of FcεRI (see, e.g., FIG. 2). This gamma chainhomodimer is shared by other Fc receptors, including FcγRI, FcγRIII andFcαRI. For all of these receptors, intracellular signal transduction ismediated by the common gamma chain homodimer. Binding and aggregation ofthose receptors results in the recruitment and activation of tyrosinekinases such as Syk kinase. As a consequence of these common signalingactivities, the 2,4-pyrimidinediamine compounds described herein may beused to regulate, and in particular inhibit, the signaling cascades ofFc receptors having this gamma chain homodimer, such as FcεRI, FcγRI,FcγRIII and FcαRI, as well as the cellular responses elicited throughthese receptors.

Syk kinase is known to play a critical role in other signaling cascades.For example, Syk kinase is an effector of B-cell receptor (BCR)signaling (Turner et al., 2000, Immunology Today 21:148-154) and is anessential component of integrin beta(1), beta(2) and beta(3) signalingin neutrophils (Mocsai et al., 2002, Immunity 16:547-558). As the2,4-pyrimidinediamine compounds described herein are potent inhibitorsof Syk kinase, they can be used to regulate, and in particular inhibit,any signaling cascade where Syk plays a role, such as, fore example, theFc receptor, BCR and integrin signaling cascades, as well as thecellular responses elicited through these signaling cascades. Theparticular cellular response regulated or inhibited will depend, inpart, on the specific cell type and receptor signaling cascade, as iswell known in the art. Non-limiting examples of cellular responses thatmay be regulated or inhibited with the 2,4-pyrimidinediamine compoundsinclude a respiratory burst, cellular adhesion, cellular degranulation,cell spreading, cell migration, phagocytosis (e.g., in macrophages),calcium ion flux (e.g., in mast, basophil, neutrophil, eosinophil andB-cells), platelet aggregation, and cell maturation (e.g., in B-cells).

Thus, in another aspect, the present invention provides methods ofregulating, and in particular inhibiting, signal transduction cascadesin which Syk plays a role. The method generally involves contacting aSyk-dependent receptor or a cell expressing a Syk-dependent receptorwith an amount of a 2,4-pyrimidinediamine compound or prodrug of theinvention, or an acceptable salt, hydrate, solvate, N-oxide and/orcomposition thereof, effective to regulate or inhibit the signaltransduction cascade. The methods may also be used to regulate, and inparticular inhibit, downstream processes or cellular responses elicitedby activation of the particular Syk-dependent signal transductioncascade. The methods may be practiced to regulate any signal trasductioncascade where Syk is not known or later discovered to play a role. Themethods may be practiced in in vitro contexts or in in vivo contexts asa therapeutic approach towards the treatment or prevention of diseasescharacterized by, caused by or associated with activation of theSyk-dependent signal transduction cascade. Non-limited examples of suchdiseases include those previously discussed.

5. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a cartoon illustrating allergen-induced production ofIgE and consequent release of preformed and other chemical mediatorsfrom mast cells;

FIG. 2 provides a cartoon illustrating the FcεRI signal transductioncascade leading to degranulation of mast and/or basophil cells;

FIG. 3 provides a cartoon illustrating the putative points of action ofcompounds that selectively inhibit upstream FcεRI-mediated degranulationand compounds that inhibit both FcεRI-mediated and ionomycin-induceddegranulation;

FIG. 4 provides graphs illustrating the effects of certain2,4-pyrimidinediamine compounds, DMSO (control) and ionomycin on Ca²⁺flux in CHMC cells;

FIG. 5 provides graphs illustrating the immediacy of the inhibitoryactivity of compounds R921218 and R926495;

FIG. 6 provides a graph illustrating the effect of washout on theinhibitory activity of compounds R921218 and R921302;

FIG. 7 provides data showing that varying concentrations of compoundsR921218 (A) and R921219 (B) inhibit phosporylation of various proteinsdownstream of Syk kinase in the IgE receptor signal transduction cascadein activated BMMC cells;

FIG. 8 provides data showing dose responsive inhibition of Syk kinasephosphorylation of an endogenous substrate (LAT) and a peptide substratein the presence of increasing concentrations of compounds R921218 (X),R921219 (Y) and R921304 (Z);

FIG. 9 provides data showing that the inhibition of Syk kinase bycompound R921219 is ATP competitive;

FIG. 10 provides data showing that varying concentrations of compoundsR921219 (A) and R218218 (B) inhibit phosphorylation of proteinsdownstream of Syk kinase, but not LYN kinase, in the FcεRI signaltransduction cascade in activated CHMC cells; also shown is inhibitionof phosphorylation of proteins downstream of LYN kinase but not Sykkinase, in the presence of a known LYN kinase inhibitor (PP2); and

FIGS. 11A-D provide data showing inhibition of phosphorylation ofproteins downstream of Syk kinase in the FcεRI signal transductioncascade in BMMC cells.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 6.1 Definitions

As used herein, the following terms are intended to have the followingmeanings:

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated branched, straight-chain or cyclic monovalenthydrocarbon radical having the stated number of carbon atoms (i.e.,C1-C6 means one to six carbon atoms) that is derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkeneor alkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Wherespecific levels of saturation are intended, the nomenclature “alkanyl,”“alkenyl” and/or “alkynyl” is used, as defined below. In preferredembodiments, the alkyl groups are (C1-C6) alkyl.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like. Inpreferred embodiments, the alkanyl groups are (C1-C6) alkanyl.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon double bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkene. The group may be in eitherthe cis or trans conformation about the double bond(s). Typical alkenylgroups include, but are not limited to, ethenyl; propenyls such asprop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, prop-2-en-2-yl,cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.;and the like. In preferred embodiments, the alkenyl group is (C2-C6)alkenyl.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl having at least onecarbon-carbon triple bond derived by the removal of one hydrogen atomfrom a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such asprop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferredembodiments, the alkynyl group is (C2-C6) alkynyl.

“Alkyldiyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic divalenthydrocarbon group having the stated number of carbon atoms (i.e., C1-C6means from one to six carbon atoms) derived by the removal of onehydrogen atom from each of two different carbon atoms of a parentalkane, alkene or alkyne, or by the removal of two hydrogen atoms from asingle carbon atom of a parent alkane, alkene or alkyne. The twomonovalent radical centers or each valency of the divalent radicalcenter can form bonds with the same or different atoms. Typicalalkyldiyl groups include, but are not limited to, methandiyl; ethyldiylssuch as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl;propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl,propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl,prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl,cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as,butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl,butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl,cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl,but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl,but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl,2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl,buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl,cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl,cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl,but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; andthe like. Where specific levels of saturation are intended, thenomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Whereit is specifically intended that the two valencies are on the samecarbon atom, the nomenclature “alkylidene” is used. In preferredembodiments, the alkyldiyl group is (C1-C6) alkyldiyl. Also preferredare saturated acyclic alkanyldiyl groups in which the radical centersare at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl(ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and thelike (also referred to as alkylenos, defined infra).

“Alkyleno” by itself or as part of another substituent refers to astraight-chain saturated or unsaturated alkyldiyl group having twoterminal monovalent radical centers derived by the removal of onehydrogen atom from each of the two terminal carbon atoms ofstraight-chain parent alkane, alkene or alkyne. The locant of a doublebond or triple bond, if present, in a particular alkyleno is indicatedin square brackets. Typical alkyleno groups include, but are not limitedto, methano; ethylenos such as ethano, etheno, ethyno; propylenos suchas propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenossuch as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno,but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels ofsaturation are intended, the nomenclature alkano, alkeno and/or alkynois used. In preferred embodiments, the alkyleno group is (C1-C6) or(C1-C3) alkyleno. Also preferred are straight-chain saturated alkanogroups, e.g., methano, ethano, propano, butano, and the like.

“Heteroalkyl,” Heteroalkanyl,” Heteroalkenyl,” Heteroalkynyl,”Heteroalkyldiyl” and “Heteroalkyleno” by themselves or as part ofanother substituent refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyland alkyleno groups, respectively, in which one or more of the carbonatoms are each independently replaced with the same or differentheteratoms or heteroatomic groups. Typical heteroatoms and/orheteroatomic groups which can replace the carbon atoms include, but arenot limited to, —O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—,—S(O)NR′—, —S(O)₂NR′—, and the like, including combinations thereof,where each R′ is independently hydrogen or (C1-C6) alkyl.

“Cycloalkyl” and “Heterocycloalkyl” by themselves or as part of anothersubstituent refer to cyclic versions of “alkyl” and “heteroalkyl”groups, respectively. For heteroalkyl groups, a heteroatom can occupythe position that is attached to the remainder of the molecule. Typicalcycloalkyl groups include, but are not limited to, cyclopropyl;cyclobutyls such as cyclobutanyl and cyclobutenyl; cyclopentyls such ascyclopentanyl and cyclopentenyl; cyclohexyls such as cyclohexanyl andcyclohexenyl; and the like. Typical heterocycloalkyl groups include, butare not limited to, tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, etc.), piperidinyl (e.g., piperidin-1-yl,piperidin-2-yl, etc.), morpholinyl (e.g., morpholin-3-yl,morpholin-4-yl, etc.), piperazinyl (e.g., piperazin-1-yl,piperazin-2-yl, etc.), and the like.

“Acyclic Heteroatomic Bridge” refers to a divalent bridge in which thebackbone atoms are exclusively heteroatoms and/or heteroatomic groups.Typical acyclic heteroatomic bridges include, but are not limited to,—O—, —S—, —S—O—, —NR′—, —PH—, —S(O)—, —S(O)₂—, —S(O)NR′—, —S(O)₂NR′—,and the like, including combinations thereof, where each R′ isindependently hydrogen or (C1-C6) alkyl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene,tetrahydronaphthalene, etc. Typical parent aromatic ring systemsinclude, but are not limited to, aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and thelike, as well as the various hydro isomers thereof.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon group having the stated number of carbonatoms (i.e., C5-C15 means from 5 to 15 carbon atoms) derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like, as well as thevarious hydro isomers thereof. In preferred embodiments, the aryl groupis (C5-C15) aryl, with (C5-C10) being even more preferred. Particularlypreferred aryls are cyclopentadienyl, phenyl and naphthyl.

“Arylaryl” by itself or as part of another substituent refers to amonovalent hydrocarbon group derived by the removal of one hydrogen atomfrom a single carbon atom of a ring system in which two or moreidentical or non-identical parent aromatic ring systems are joineddirectly together by a single bond, where the number of such direct ringjunctions is one less than the number of parent aromatic ring systemsinvolved. Typical arylaryl groups include, but are not limited to,biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, andthe like. Where the number of carbon atoms in an arylaryl group arespecified, the numbers refer to the carbon atoms comprising each parentaromatic ring. For example, (C5-C15) arylaryl is an arylaryl group inwhich each aromatic ring comprises from 5 to 15 carbons, e.g., biphenyl,triphenyl, binaphthyl, phenylnaphthyl, etc. Preferably, each parentaromatic ring system of an arylaryl group is independently a (C5-C15)aromatic, more preferably a (C5-C10) aromatic. Also preferred arearylaryl groups in which all of the parent aromatic ring systems areidentical, e.g., biphenyl, triphenyl, binaphthyl, trinaphthyl, etc.

“Biaryl” by itself or as part of another substituent refers to anarylaryl group having two identical parent aromatic systems joineddirectly together by a single bond. Typical biaryl groups include, butare not limited to, biphenyl, binaphthyl, bianthracyl, and the like.Preferably, the aromatic ring systems are (C5-C15) aromatic rings, morepreferably (C5-C10) aromatic rings. A particularly preferred biarylgroup is biphenyl.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylakenyl and/orarylalkynyl is used. In preferred embodiments, the arylalkyl group is(C6-C21) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C1-C6) and the aryl moiety is (C5-C15). Inparticularly preferred embodiments the arylalkyl group is (C6-C13),e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C1-C3) and the aryl moiety is (C5-C10).

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms are each independently replacedwith the same or different heteroatoms or heteroatomic groups. Typicalheteroatoms or heteroatomic groups to replace the carbon atoms include,but are not limited to, N, NH, P, O, S, S(O), S(O)₂, Si, etc.Specifically included within the definition of “parent heteroaromaticring systems” are fused ring systems in which one or more of the ringsare aromatic and one or more of the rings are saturated or unsaturated,such as, for example, benzodioxan, benzofuran, chromane, chromene,indole, indoline, xanthene, etc. Also included in the definition of“parent heteroaromatic ring system” are those recognized rings thatinclude common substituents, such as, for example, benzopyrone and1-methyl-1,2,3,4-tetrazole. Specifically excluded from the definition of“parent heteroaromatic ring system” are benzene rings fused to cyclicpolyalkylene glycols such as cyclic polyethylene glycols. Typical parentheteroaromatic ring systems include, but are not limited to, acridine,benzimidazole, benzisoxazole, benzodioxan, benzodioxole, benzofuran,benzopyrone, benzothiadiazole, benzothiazole, benzotriazole,benzoxaxine, benzoxazole, benzoxazoline, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic group having the stated number of ring atoms(e.g., “5-14 membered” means from 5 to 14 ring atoms) derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, benzimidazole,benzisoxazole, benzodioxan, benzodiaxole, benzofuran, benzopyrone,benzothiadiazole, benzothiazole, benzotriazole, benzoxazine,benzoxazole, benzoxazoline, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike, as well as the various hydro isomers thereof. In preferredembodiments, the heteroaryl group is a 5-14 membered heteroaryl, with5-10 membered heteroaryl being particularly preferred.

“Heteroaryl-Heteroaryl” by itself or as part of another substituentrefers to a monovalent heteroaromatic group derived by the removal ofone hydrogen atom from a single atom of a ring system in which two ormore identical or non-identical parent heteroaromatic ring systems arejoined directly together by a single bond, where the number of suchdirect ring junctions is one less than the number of parentheteroaromatic ring systems involved. Typical heteroaryl-heteroarylgroups include, but are not limited to, bipyridyl, tripyridyl,pyridylpurinyl, bipurinyl, etc. Where the number of atoms are specified,the numbers refer to the number of atoms comprising each parentheteroaromatic ring systems. For example, 5-15 memberedheteroaryl-heteroaryl is a heteroaryl-heteroaryl group in which eachparent heteroaromatic ring system comprises from 5 to 15 atoms, e.g.,bipyridyl, tripuridyl, etc. Preferably, each parent heteroaromatic ringsystem is independently a 5-15 membered heteroaromatic, more preferablya 5-10 membered heteroaromatic. Also preferred are heteroaryl-heteroarylgroups in which all of the parent heteroaromatic ring systems areidentical.

“Biheteroaryl” by itself or as part of another substituent refers to aheteroaryl-heteroaryl group having two identical parent heteroaromaticring systems joined directly together by a single bond. Typicalbiheteroaryl groups include, but are not limited to, bipyridyl,bipurinyl, biquinolinyl, and the like. Preferably, the heteroaromaticring systems are 5-15 membered heteroaromatic rings, more preferably5-10 membered heteroaromatic rings.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C1-C6) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In particularlypreferred embodiments, the heteroarylalkyl is a 6-13 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1-C3)alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

“Halogen” or “Halo” by themselves or as part of another substituent,unless otherwise stated, refer to fluoro, chloro, bromo and iodo.

“Haloalkyl” by itself or as part of another substituent refers to analkyl group in which one or more of the hydrogen atoms is replaced witha halogen. Thus, the term “haloalkyl” is meant to includemonohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls.For example, the expression “(C1-C2) haloalkyl” includes fluoromethyl,difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl,1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

The above-defined groups may include prefixes and/or suffixes that arecommonly used in the art to create additional well-recognizedsubstituent groups. As examples, “alkyloxy” or “alkoxy” refers to agroup of the formula —OR″, “alkylamine” refers to a group of the formula—NHR″ and “dialkylamine” refers to a group of the formula —NR″R″, whereeach R″ is independently an alkyl. As another example, “haloalkoxy” or“haloalkyloxy” refers to a group of the formula —OR′″, where R′″ is ahaloalkyl.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd) Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative aminoprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxylprotecting groups include,but are not lirnited to, those where the hydroxyl group is eitheracylated or alkylated such as benzyl and trityl ethers, as well as alkylethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS orTIPPS groups) and allyl ethers.

“Prodrug” refers to a derivative of an active 2,4-pyrimidinediaminecompound (drug) that requires a transformation under the conditions ofuse, such as within the body, to release the active2,4-pyrimidinediamine drug. Prodrugs are frequently, but notnecessarily, pharmacologically inactive until converted into the activedrug. Prodrugs are typically obtained by masking a functional group inthe 2,4-pyrimidinediamine drug believed to be in part required foractivity with a progroup (defined below) to form a promoiety whichundergoes a transformation, such as cleavage, under the specifiedconditions of use to release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it may becatalyzed or induced by another agent, such as by an enzyme, by light,by acid or base, or by a change of or exposure to a physical orenvironmental parameter, such as a change of temperature. The agent maybe endogenous to the conditions of use, such as an enzyme present in thecells to which the prodrug is administered or the acidic conditions ofthe stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in the active2,4-pyrimidinediamines compounds to yield prodrugs are well-known in theart. For example, a hydroxyl functional group may be masked as asulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivoto provide the hydroxyl group. An amino functional group may be maskedas an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenylpromoiety, which may be hydrolyzed in vivo to provide the amino group. Acarboxyl group may be masked as an ester (including silyl esters andthioesters), amide or hydrazide promoiety, which may be hydrolyzed invivo to provide the carboxyl group. Other specific examples of suitableprogroups and their respective promoieties will be apparent to those ofskill in the art.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Fc Receptor” refers to a member of the family of cell surface moleculesthat binds the Fc portion (containing the specific constant region) ofan immunoglobulin. Each Fc receptor binds immunoglobulins of a specifictype. For example the Fcα receptor (“FcαR”) binds IgA, the FcεR bindsIgE and the FcγR binds IgG.

The FcαR family includes the polymeric Ig receptor involved inepithelial transport of IgA/IgM, the mycloid specific receptor RcαRI(also called CD89), the Fcα/μR and at least two alternative IgAreceptors (for a recent review see Monteiro & van de Winkel, 2003, Annu.Rev. Immunol, advanced e-publication. The FcαRI is expressed onneutrophils, eosinophils, moncytes/macrophages, dendritic cells andkupfer cells. The FcαRI includes one alpha chain and the FcR gammahomodimer that bears an activation motif (ITAM) in the cytoplasmicdomain and phosphorylates Syk kinase.

The FcεRI family includes two types, designated FcεRI and FcεRII (alsoknown as CD23). FcεRI is a high affinity receptor (binds IgE with anaffinity of about 10¹⁰M⁻¹) found on mast, basophil and eosinophil cellsthat anchors monomeric IgE to the cell surface. The FcεRI possesses onealpha chain, one beta chain and the gamma chain homodimer discussedabove. The FcεRII is a low affinity receptor expressed on mononuclearphagocytes, B lymphocytes, eosinophils and platelets. The FcεRIIcomprises a single polypeptide chain and does not include the gammachain homodimer.

The FcγR family includes three types, designated FcγRI (also known asCD64), FcγRII (also known as CD32) and FcγRIII (also known as CD16).FcγRI is a high affinity receptor (binds IgG1 with an affinity of10⁸M⁻¹) found on mast, basophil, mononuclear, neutrophil, eosinophil,deudritic and phagocyte cells that anchors nomomeric IgG to the cellsurface. The FcγRI includes one alpha chain and the gamma chain dimershared by FcαRI and FcεRI.

The FcγRII is a low affinity receptor expressed on neutrophils,monocytes, eosinophils, platelets and B lymphocytes. The FcγRII includesone alpha chain, and does not include the gamma chain homodimerdiscussed above.

The FcγRIII is a low affinity (bindes IgG1 with an affinity of 5×10⁵M⁻¹)expressed on NK, eosinophil, macrophage, neutrophil and mast cells. Itcomprises one alpha chain and the gamma homodimer shared by FcαRI, FcεRIand FcγRI.

Skilled artisans will recognize that the subunit structure and bindingproperties of these various Fc receptors, cell types expressing them,are not completely characterized. The above discussion merely reflectsthe current state-of-the-art regarding these receptors (see, e.g.,Immunobiology: The Immune System in Health & Disease, 5^(th) Edition,Janeway et al., Eds, 2001, ISBN 0-8153-3642-x, FIG. 9. 30 at pp. 371),and is not intended to be limiting with respect to the myriad receptorsignaling cascades that can be regulated with the compounds describedherein.

“Fc Receptor-Mediated Degranulation” or “Fc Receptor-InducedDegranulation” refers to degranulation that proceeds via an Fc receptorsignal transduction cascade initiated by crosslinking of an Fc receptor.

“IgE-Induced Degranulation” or “FcεRI-Mediated Degranulation” refers todegranulation that proceeds via the IgE receptor signal transductioncascade initiated by crosslinking of FcεRI-bound IgE. The crosslinkingmay be induced by an IgE-specific allergen or other multivalent bindingagent, such as an anti-IgE antibody. Referring to FIG. 2, in mast and/orbasophil cells, the FcεRI signaling cascade leading to degranulation maybe broken into two stages: upstream and downstream. The upstream stageincludes all of the processes that occur prior to calcium ionmobilization (illustrated as “Ca²⁺” in FIG. 2; see also FIG. 3). Thedownstream stage includes calcium ion mobilization and all processesdownstream thereof. Compounds that inhibit FcεRI-mediated degranulationmay act at any point along the FcεRI-mediated signal transductioncascade. Compounds that selectively inhibit upstream FcεRI-mediateddegranulation act to inhibit that portion of the FcεRI signaling cascadeupstream of the point at which calcium ion mobilization is induced. Incell-based assays, compounds that selectively inhibit upstreamFcεRI-mediated degranulation inhibit degranulation of cells such as mastor basophil cells that are activated or stimulated with an IgE-specificallergen or binding agent (such as an anti-IgE antibody) but do notappreciably inhibit degranulation of cells that are activated orstimulated with degranulating agents that bypass the FcεRI signalingpathway, such as, for example the calcium ionophores ionomycin andA23187.

“IgG-Induced Degranulation” or “FcγRI-Mediated Degranulation” refers todegranulation that proceeds via the FcγRI signal transduction cascadeinitiated by crosslinking of FcγRI-bound IgG. The crosslinking may beinduced by an IgG-specific allergen or another multivalent bindingagent, such as an anti-IgG or fragment antibody. Like the FcεRIsignaling cascade, in mast and basophil cells the FcγRI signalingcascade also leads to degranulation which may be broken into the sametwo stages: upstream and downstream. Similar to FcεRI-mediateddegranulation, compounds that selectively inhibit upstreamFcγRI-mediated degranulation act upstream of the point at which calciumion mobilization is induced. In cell-based assays, compounds thatselectively inhibit upstream FcγRI-mediated degranulation inhibitdegranulation of cells such as mast or basophil cells that are activatedor stimulated with an IgG-specific allergen or binding agent (such as ananti-IgG antibody or fragment) but do not appreciably inhibitdegranulation of cells that are activated or stimulated withdegranulating agents that bypass the FcγRI signaling pathway, such as,for example the calcium ionophores ionomycin and A23187.

“Ionophore-Induced Degranulation” or “Ionophore-Mediated Degranulation”refers to degranulation of a cell, such as a mast or basophil cell, thatoccurs upon exposure to a calcium ionophore such as, for example,ionomycin or A23187.

“Syk Kinsase” refers to the well-known 72 kDa non-receptor (cytoplasmic)spleen protein tyrosine kinase expressed in B-cells and otherhematopoetic cells. Syk kinase includes two consensus Src-homology 2(SH2) domains in tandem that bind to phosphorylated immunoreceptortyrosine-based activation motifs (“ITAMs”), a “linker” domain and acatalytic domain (for a review of the structure and function of Sykkinase see Sada et al., 2001, J. Biochem. (Tokyo) 130:177-186); see alsoTurner et al., 2000, Immunology Today 21:148-154). Syk kinase has beenextensively studied as an effector of B-cell receptor (BCR) signaling(Turner et al., 2000, supra). Syk kinase is also critical for tyrosinephosphorylation of multiple proteins which regulate important pathwaysleading from immunoreceptors, such as Ca²⁺ mobilization andmitogen-activated protein kinase (MAPK) cascades (see, e.g., FIG. 2) anddegranulation. Syk kinase also plays a critical role in integrinsignaling in neutrophils (see, e.g., Mocsai et al. 2002, Immunity16:547-558).

As used herein, Syk kinase includes kinases from any species of animal,including but not limited to, homosapiens, simian, bovine, porcine,rodent, etc., recognized as belonging to the Syk family. Specificallyincluded are isoforms, splice variants, allelic variants, mutants, bothnaturally occuring and man-made. The amino acid sequences of such Sykkinases are well known and available from GENBANK. Specific examples ofmRNAs encoding different isoforms of human Syk kinase can be found atGENBANK accession no. gi|21361552|ref|NM_(—)003177.2|,gi|496899|emb|Z29630.1|HSSYKPTK[496899] andgi|15030258|gb|BC011399.1|BC011399[15030258], which are incorporatedherein by reference.

Skilled artisans will appreciate that tyrosine kinases belonging toother families may have active sites or binding pockets that are similarin three-dimensional structure to that of Syk. As a consequence of thisstructural similarity, such kinases, referred to herein as “Syk mimics,”are expected to catalyze phosphorylation of substrates phosphorylated bySyk. Thus, it will be appreciated that such Syk mimics, signaltransduction cascades in which such Syk mimics play a role andbiological responses effected by such Syk mimics and Syk mimic-dependentsignaling cascades may be regulated, and in particular inhibited, withthe 2,4-pyrimidinediamine compounds described herein.

“Syk-Dependent Signaling Cascade” refers to a signal transductioncascade in which Syk kinase plays a role. Non-limiting examples of suchSyk-dependent signaling cascades include the FcαRI, FcεRI, FcγRI,FcγRIII, BCR and integrin signaling cascades.

6.2 The 2,4-Pyrimidinediamine Compounds

The compounds of the invention are generally 2,4-pyrimidinediaminecompounds according to structural formula (I):

including salts, hydrates, solvates and N-oxides thereof, wherein:

L¹ and L² are each, independently of one another, selected from thegroup consisting of a direct bond and a linker;

R² is selected from the group consisting of (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C3-C8)cycloalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, cyclohexyl optionally substituted with one or moreof the same or different R⁸ groups, 3-8 membered cycloheteroalkyloptionally substituted with one or more of the same or different R⁸groups, (C5-C15) aryl optionally substituted with one or more of thesame or different R⁸ groups, phenyl optionally substituted with one ormore of the same or different R⁸ groups and 5-15 membered heteroaryloptionally substituted with one or more of the same or different R⁸groups;

R⁴ is selected from the group consisting of hydrogen, (C1-C6) alkyloptionally substituted with one or more of the same or different R⁸groups, (C3-C8) cycloalkyl optionally substituted with one or more ofthe same or different R⁸ groups, cyclohexyl optionally substituted withone or more of the same or different R⁸ groups, 3-8 memberedcycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, (C5-C15) aryl optionally substituted with one ormore of the same or different R⁸ groups, phenyl optionally substitutedwith one or more of the same or different R⁸ groups and 5-15 memberedheteroaryl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁵ is selected from the group consisting of R⁶, (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups, (C1-C4)alkanyl optionally substituted with one or more of the same or differentR⁸ groups, (C2-C4) alkenyl optionally substituted with one or more ofthe same or different R⁸ groups and (C2-C4) alkynyl optionallysubstituted with one or more of the same or different R⁸ groups;

each R⁶ is independently selected from the group consisting of hydrogen,an electronegative group, —OR^(d), —SR^(d), (C1-C3) haloalkyloxy,(C1-C3) perhaloalkyloxy, —NR^(c)R^(c), halogen, (C1-C3)haloalkyl,(C1-C3) perhaloalkyl, —CF₃, —CH₂CF₃, —CF₂CF₃, —CN, —NC, —OCN,—SCN, —NO, —NO₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)NR^(c)R^(c), —OS(O)₂NR^(c)R^(c), —C(O)R^(d),—C(O)OR^(d), —C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —OC(O)R^(d),—SC(O)R^(d), —OC(O)OR^(d), —SC(O)OR^(d), —OC(O)NR^(c)R^(c),—SC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —SC(NH)NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c) and—[NHC(NH)]_(n)NR^(c)R^(c), (C5-C10) aryl optionally substituted with oneor more of the same or different R⁸ groups, phenyl optionallysubstituted with one or more of the same or different R⁸ groups,(C6-C16) arylalkyl optionally substituted with one or more of the sameor different R⁸ groups, 5-10 membered heteroaryl optionally substitutedwith one or more of the same or different R⁸ groups and 6-16 memberedheteroarylalkyl optionally substituted with one or more of the same ordifferent R⁸ groups;

R⁸ is selected from the group consisting of R^(a), R^(b), R^(a)substituted with one or more of the same or different R^(a) or R^(b),—OR^(a) substituted with one or more of the same or different R^(a) orR^(b), —B(OR^(a))₂, —B(NR^(c)R^(c))₂, —(CH₂)_(m)—R^(b),—(CHR^(a))_(m)—R^(b), —O—(CH₂)_(m)—R_(b), —S—(CH₂)_(m)—R^(b),—O—CHR^(a)R^(b), —O—CR^(a)(R^(b))₂, —O—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—CH[(CH₂)_(m)R^(b)]R^(b), —S—(CHR^(a))_(m)—R^(b),—C(O)NH—(CH₂)_(m)—R^(b), —C(O)NH—(CHR^(a))_(m)—R^(b),—O—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—S—(CH₂)_(m)—C(O)NH—(CH₂)_(m)—R^(b),—O—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b),—S—(CHR^(a))_(m)—C(O)NH—(CHR^(a))_(m)—R^(b), —NH—(CH₂)_(m)—R^(b),—NH—(CHR^(a))_(m)—R^(b), —NH[(CH₂)_(m)R^(b)], —N[(CH₂)_(m)R^(b)]₂,—NH—C(O)—NH—(CH₂)_(m)—R^(b), —NH—C(O)—(CH₂)_(m)—CHR^(b)R^(b) and—NH—(CH₂)_(m)—C(O)—NH—(CH₂)_(m)—R^(b);

each R^(a) is independently selected from the group consisting ofhydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11)cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl,piperazinyl, homopiperazinyl, piperidinyl, 4-11 memberedcycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 memberedheteroarylalkyl;

each R^(b) is a suitable group independently selected from the groupconsisting of ═O, —OR^(d), (C1-C3) haloalkyloxy, —OCF₃, ═S, —SR^(d),═NR^(d), ═NOR^(d), —NR^(c)R^(c), halogen, —CF₃, —CN, —NC, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)R^(d), —S(O)₂R^(d), —S(O)₂OR^(d),—S(O)NR^(c)R^(c), —S(O)₂NR^(c)R^(c), —OS(O)R^(d), —OS(O)₂R^(d),—OS(O)₂OR^(d), —OS(O)₂NR^(c)R^(c), —C(O)R^(d), —C(O)OR^(d),—C(O)NR^(c)R^(c), —C(NH)NR^(c)R^(c), —C(NR^(a))NR^(c)R^(c),—C(NOH)R^(a), —C(NOH)NR^(c)R^(c), —OC(O)R^(d), —OC(O)OR,—OC(O)NR^(c)R^(c), —OC(NH)NR^(c)R^(c), —OC(R^(a))NR^(c)R^(c),—[NHC(O)]_(n)R^(d), —[NR^(a)C(O)]_(n)R^(d), —[NHC(O)]_(n)OR^(d),—[NR^(a)C(O)]_(n)OR^(d), —[NHC(O)]_(n)NR^(c)R^(c),—[NR^(a)C(O)]_(n)NR^(c)R^(c), —[NHC(NH)]_(n)NR^(c)R^(c) and—[NR^(a)C(NR^(a))]_(n)NR^(c)R^(c);

each R^(c) is independently R^(a), or, alternatively, each R^(c) istaken together with the nitrogen atom to which it is bonded to form a 5to 8-membered cycloheteroalkyl or heteroaryl which may optionallyinclude one or more of the same or different additional heteroatoms andwhich is optionally substituted with one or more of the same ordifferent R^(a) or suitable R^(b) groups;

each R^(d) is independently R^(a);

each m is independently an integer from 1 to 3; and

each n is independently an integer from 0 to 3.

In the compounds of structural formula (I), L¹ and L² represent,independently of one another, a direct bond or a linker. Thus, as willbe appreciated by skilled artisans, the substituents R² and/or R⁴ may bebonded either directly to their respective nitrogen atoms or,alternatively, spaced away from their respective nitrogen atoms by wayof a linker. The identity of the linker is not critical and typicalsuitable linkers include, but are not limited to, (C1-C6) alkyldiyls,(C1-C6) alkanos and (C1-C6) heteroalkyldiyls, each of which may beoptionally substituted with one or more of the same or different R⁸groups, where R⁸ is as previously defined for structural formula (I). Ina specific embodiment, L¹ and L² are each, independently of one another,selected from the group consisting of a direct bond, (C1-C3) alkyldiyloptionally substituted with one or more of the same or different R^(a),suitable R^(b) or R⁹ groups and 1-3 membered heteroalkyldiyl optionallysubstituted with one or more of the same or different R^(a), suitableR^(b) or R⁹ groups, wherein R⁹ is selected from the group consisting of(C1-C3) alkyl, —OR^(a), —C(O)OR^(a), (C5-C10) aryl optionallysubstituted with one or more of the same or different halogens, phenyloptionally substituted with one or more of the same or differenthalogens, 5-10 membered heteroaryl optionally substituted with one ormore of the same or different halogens and 6 membered heteroaryloptionally substituted with one or more of the same or differenthalogens; and R^(a) and R^(b) are as previously defined for structuralformula (I). Specific R⁹ groups that may be used to substitute L¹ and L²include —OR^(a), —C(O)OR^(a), phenyl, halophenyl and 4-halophenyl,wherein R^(a) is as previously defined for structural formula (I).

In another specific embodiment, L¹ and L² are each, independently of oneanother, selected from the group consisting of methano, ethano andpropano, each of which may be optionally monosubstituted with an R⁹group, where R⁹ is as previously defined above.

In all of the above embodiments, specific R^(a) groups that may beincluded in R⁹ groups are selected from the group consisting ofhydrogen, (C1-C6) alkyl, phenyl and benzyl.

In still another specific embodiment, L¹ and L² are each a direct bondsuch that the 2,4-pyrimidinediamine compounds of the invention arecompounds according to structural formula (Ia):

including salts, hydrates, solvates and N-oxides thereof, wherein R²,R⁴, R⁵ and R⁶ are as previously defined for structural formula (I).Additional specific embodiments of the 2,4-pyrimidinediamine compoundsof the invention are described below.

In a first embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for theirrespective structures (I) and (Ia), with the proviso that R² is not3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6) alkoxyphenyl or

where R²¹, R²² and R²³ are as defined for R¹, R² and R³, respectively ofU.S. Pat. No. 6,235,746, the disclosure of which is incorporated byreference. In a specific embodiment of this first embodiment, R²¹ ishydrogen, halo, straight-chain or branched (C1-C6) alkyl optionallysubstituted with one or more of the same or different R²⁵ groups,hydroxyl, (C1-C6) alkoxy optionally substituted with one or more of thesame or different phenyl or R²⁵ groups, thiol (—SH), (C1-C6) alkylthiooptionally substituted with one or more of the same or different phenylor R²⁵ groups, amino (—NH₂), —NHR²⁶ or —NR²⁶R²⁶; R²² and R²³ are each,independently of one another, a (C1-C6) straight-chain or branched alkyloptionally substituted with one or more of the same or different R²⁵groups; R²⁵ is selected from the group consisting of halo, hydroxyl,(C1-C6) alkoxy, thiol, (C1-C6) alkylthio, (C1-C6) alkylamino and (C1-C6)dialkylamino; and each R²⁶ is independently a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups or a —C(O)R²⁷, where R²⁷ is a (C1-C6) alkyl optionallysubstituted with one or more of the same or different phenyl or R²⁵groups.

In another specific embodiment of this first embodiment, R²¹ is methoxyoptionally substituted with one or more of the same or different halogroups and/or R²² and R²³ are each, independently of one another, amethyl or ethyl optionally substituted with one or more of the same ordifferent halo groups.

In a second embodiment of the compounds of structural formulae (I) and(Ia), R², R⁴, R⁵ and L² are as previously described for their respectivestructures (I) and (Ia), L¹ is a direct bond and R⁶ is hydrogen, withthe proviso that R² is not 3,4,5-trimethoxyphenyl, 3,4,5-tri (C1-C6)alkoxyphenyl or

where R²¹, R²² and R²³ are as defined above, in connection with thefirst embodiment.

In a third embodiment, the 2,4-pyrimidinediamine compounds of structuralformulae (I) and (Ia) exclude one or more of the following compounds:

-   N2,N4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R070790);-   N2,N4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R081166);-   N2,N4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (R088814);-   N2,N4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R088815);-   N2,N4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (R091880);-   N2,N4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (R092788);-   N2,N4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R067962);-   N2,N4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine    (R067963);-   N2,N4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine    (R067964);-   N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (R0707153);-   N2,N4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine    (R070791);-   N2,N4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (R008958);-   N2,N4-bis(phenyl)-5-fluoro-2,4-pyrimidinediamine;-   N2,N4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and-   N2,N4-bis[(3-chloro-4-methoxyphenyl)]-5-fluoro-2,4-pyrimidinediamine.

In a fourth embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds according to the following structural formula(Ib):

wherein R²⁴ is (C1-C6) alkyl; and R²¹, R²² and R²³ are as previouslydefined in connection with the first embodiment.

In a fifth embodiment, the compounds of structural formulae (I) and (Ia)exclude the compounds described in Examples 1-141 of U.S. Pat. No.6,235,746, the disclosure of which is incorporated herein by reference.

In a sixth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds defined by formula (1) or formula 1(a) of this U.S.Pat. No. 6,235,746 (see, e.g., the disclosure at Col. 1, line 48 throughCol. 7, line 49 and Col. 8, lines 9-36, which is incorporated byreference).

In a seventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds in which R⁵ is cyano or —C(O)NHR, where R ishydrogen or (C1-C6) alkyl, when R² is a substituted phenyl; R4 is asubstituted or unsubstituted (C1-C6) alkyl, (C3-C8) cycloalkyl, 3-8membered cycloheteralkyl or 5-15 membered heteroaryl; and R⁶ ishydrogen.

In an eighth embodiment, the compounds of structural formulae (I) and(Ia) exclude the compounds defined by formulae (I) and (X) of WO02/04429 or any compound disclosed in WO 02/04429, the disclosure ofwhich is incorporated herein by reference.

In a ninth embodiment of the compounds of structural formulae (I) and(Ia), when R⁵ is cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl; and R⁶ is hydrogen, then R² is other than a substituted phenylgroup.

In a tenth embodiment, the compounds of structural formulae (I) and (Ia)exclude compounds in which R² and R⁴ are each independently asubstituted or unsubstituted pyrrole or indole ring which is attached tothe remainder of the molecule via its ring nitrogen atom.

In an eleventh embodiment, the compounds of structural formulae (I) and(Ia) exclude compounds defined by formulae (I) and (TV) of U.S. Pat. No.4,983,608 or any compound disclosed in U.S. Pat. No. 4,983,608, thedisclosure of which is incorporated herein by reference.

Those of skill in the art will appreciate that in the compounds offormulae (I) and (Ia), R² and R⁴ may be the same or different, and mayvary broadly. When R² and/or R⁴ are optionally substituted rings, suchas optionally substituted cycloalkyls, cycloheteroalkyls, aryls andheteroaryls, the ring may be attached to the remainder of the moleculethrough any available carbon or heteroatom. The optional substituentsmay be attached to any available carbon atoms and/or heteroatoms.

In a twelfth embodiment of the compounds of structural formulae (I) and(Ia), R² and/or R⁴ is an optionally substituted phenyl or an optionallysubstituted (C5-C15) aryl, subject to the provisos that (1) when R⁶ ishydrogen, then R² is not 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1-C6)alkoxyphenyl; (2) when R² is a 3,4,5-trisubstituted phenyl, then thesubstituents at the 3- and 4-positions are not simultaneously methoxy or(C1-C6) alkoxy; or (3) when R⁶ is hydrogen and R⁴ is (C1-C6) alkyl,(C3-C8) cycloalkyl, 3-8 membered cycloheteroalkyl or 5-15 memberedheteroaryl, then R⁵ is other than cyano. Alternatively, R² is subject tothe provisos described in connection with the first or secondembodiments. The optionally substituted aryl or phenyl group may beattached to the remainder of the molecule through any available carbonatom. Specific examples of optionally substituted phenyls includephenyls that are optionally mono-, di- or tri-substituted with the sameor different R⁸ groups, where R⁸ is as previously defined for structuralformula (I) and subject to the above provisos. When the phenyl ismono-substituted, the R⁹ substituent may be positioned at either theortho, meta or para position. When positioned at the ortho, meta or paraposition, R⁸ is preferably selected from the group consisting of(C1-C10) alkyl, (C1-C10) branched alkyl, —OR^(a) optionally substitutedwith one or more of the same or different R^(b) groups, —O—C(O)OR^(a),—O—(CH₂)_(m)—C(O)OR^(a), —C(O)OR^(a), —O—(CH₂)_(m)—NR^(c)R^(c),—O—C(O)NR^(c)R^(c), —O—(CH₂)_(m)—C(O)NR^(c)R^(c), —O—C(NH)NR^(c)R^(c),—O—(CH₂)_(m)—C(NH)NR^(c)R^(c) and —NH—(CH₂)_(m)—NR^(c)R^(c), where m,R^(a) and R^(c) are as previously defined for structural formula (I). Inone embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedheteroaryl which optionally includes one or more of the same ordifferent additional heteroatoms. Specific examples of such 5-6 memberedheteroaryls include, but are not limited to, oxadiazolyl, triazolyl,thiazolyl, oxazolyl, tetrazolyl and isoxazolyl.

In another embodiment of these compounds, —NR^(c)R^(c) is a 5-6 memberedsaturated cycloheteroalkyl ring which optionally includes one or more ofthe same or different heteroatoms. Specific examples of suchcycloheteroalkyls include, but are not limited to, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl and morpholinyl.

In still another embodiment of these compounds, each R^(a) isindependently a (C1-C6) alkyl and/or each —NR^(c)R^(c) is —NHR^(a),where R^(a) is a (C1-C6) alkyl. In one specific embodiment, R⁸ is—O—CH₂—C(O)NHCH₃. In another specific embodiment R⁸ is —OH.

When the phenyl is di-substituted or tri-substituted, the R⁸substituents may be positioned at any combination of positions. Forexample, the R⁸ substituents may be positioned at the 2,3-, 2,4-, 2,5-,2,6-, 3,4-, 3,5-, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or3,4,5-positions. In one embodiment of compounds including adisubstituted phenyl, the substituents are positioned other than 3,4. Inanother embodiment they are positioned 3,4. In one embodiment ofcompounds including a trisubstituted phenyl, the substituents arepositioned other than 3,4,5 or, alternatively, no two of thesubstituents are positioned 3,4. In another embodiment, the substituentsare positioned 3,4,5.

Specific examples of R⁸ substituents in such di- and trisubstitutedphenyls include the various R⁸ substituents described above inconnection with the ortho, meta and para substituted phenyls.

In another specific embodiment, R⁸ substituents useful forsubstitituting such di-and trisubstituted phenyls include (C1-C6) alkyl,(C1-C6) alkoxy, methoxy, halo, chloro, (C1-C6) perhaloalkyl, —CF₃,(C1-C6) perhaloalkoxy and —OCF₃. In a preferred embodiment, such R⁸substituents are positioned 3, 4 or 3,5. Specific examples of preferreddi-substituted phenyl rings include 3-chloro-4-methoxy-phenyl,3-methoxy-4-chlorophenyl, 3-chloro-4-trifluoromethoxy-phenyl,3-trifluoromethoxy-4-chloro-phenyl, 3,4-dichloro-phenyl,3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl, with the provisos that: (1)when R⁴ is one of the above-identified phenyls, and R⁵ and R⁶ are eachhydrogen, then R² is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl; (2) when R² is 3,4-dimethoxyphenyl and R⁵ and R⁶are each hydrogen, then R4 is not 3-(C1-C6)alkoxyphenyl,3-methoxyphenyl, 3,4-di-(C1-C6) alkoxyphenyl or 3,4-dimethoxyphenyl; (3)when R⁴ is 3-chloro-4-methoxyphenyl and R⁵ is halo or fluoro, andoptionally R⁶ is hydrogen, then R² is not 3-chloro-4-(C1-C6)alkoxyphenylor 3-chloro-4-methoxyphenyl; (4) when R⁴ is 3,4-dichlorophenyl, R⁵ ishydrogen, (C1-C6) alkyl, methyl, halo or chloro and optionally R⁶ ishydrogen, then R² is not a phenyl mono substituted at the para positionwith a (C1-C6) alkoxy group which is optionally substituted with one ormore of the same or different R^(b), —OH or —NR^(c)R^(c) groups, whereR^(b) and R^(c) are as previously described for structural formula (I);and/or (5) R² and/or R⁴ is not 3,4,5-tri(C1-C6)alkoxyphenyl or3,4,5-trimethoxyphenyl, especially when R⁵ and R⁶ are each hydrogen.

In another embodiment of compounds including a trisubstituted phenyl,the trisubstituted phenyl has the formula:

wherein: R³¹ is methyl or (C1-C6) alkyl; R³² is hydrogen, methyl or(C1-C6) alkyl; and R³³ is a halo group.

In a thirteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and/or R⁴ is an optionally substituted heteroaryl. Typicalheteroaryl groups according to this thirteenth embodiment comprise from5 to 15, and more typically from 5 to 11 ring atoms, and include one,two, three or four of the same or different heteratoms or heteroatomicgroups selected from the group consisting of N, NH, O, S, S(O) andS(O)₂. The optionally substituted heteroaryl may be attached to itsrespective C2 or C4 nitrogen atom or linker L¹ or L² through anyavailable carbon atom or heteroatom, but is typically attached via acarbon atom. The optional substituents may be the same or different, andmay be attached to any available carbon atom or heteroatom. In oneembodiment of these compounds, R⁵ is other than bromo, nitro,trifluoromethyl, cyano or —C(O)NHR, where R is hydrogen or (C1-C6)alkyl. In another embodiment of these compounds, when R² and R⁴ are eacha substituted or unsubstituted pyrrole or indole, then the ring isattached to the remainder of the molecule via a ring carbon atom. Instill another embodiment of compounds including an optionallysubstituted heteroaryl group, the heteroaryl is unsubstituted orsubstituted with from one to four of the same or different R⁸ groups,where R⁸ is as previously defined for structural formula (I). Specificexamples of such optionally substituted heteroaryls include, but are notlimited to, the following heteroaryl groups:

wherein:

-   -   p is an integer from one to three;    -   each

-   -    independently represents a single bond or a double bond;    -   R³⁵ is hydrogen or R⁸, where R⁸ is as previously defined for        structural formula (I);    -   X is selected from the group consisting of CH, N and N—O;    -   each Y is independently selected from the group consisting of O,        S and NH;    -   each Y¹ is independently selected from the group consisting of        O, S, SO, SO₂, SONR³⁶, NH and NR³⁷;    -   each Y² is independently selected from the group consisting of        CH, CH₂, O, S, N, NH and NR³⁷;    -   R³⁶ is hydrogen or alkyl;    -   R³⁷ is selected from the group consisting of hydrogen and a        progroup, preferably hydrogen or a progroup selected from the        group consisting of aryl, arylalkyl, heteroaryl, R^(a),        R^(b)—CR^(a)R^(b)—O—C(O)R⁸, —CR^(a)R^(b)—O—PO(OR⁸)₂,        —CH₂—O—PO(OR⁸)₂, —CH₂—PO(OR⁸)₂, —C(O)—CR^(a)R^(b)—N(CH₃)₂,        —CR^(a)R^(b)—O—C(O)—CR^(a)R^(b)—N(CH₃)₂, —C(O)R⁸, —C(O)CF₃ and        —C(O)—NR⁸—C(O)R⁸;    -   A is selected from the group consisting of O, NH and NR³⁸;    -   R³⁸ is selected from the group consisting of alkyl and aryl;    -   R⁹, R¹⁰, R¹¹ and R¹² are each, independently of one another,        selected from the group consisting of alkyl, alkoxy, halogen,        haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R⁹        and R¹⁰ and/or R¹¹ and R¹² are taken together form a ketal;    -   each Z is selected from the group consisting of hydroxyl,        alkoxy, aryloxy, ester, carbamate and sulfonyl;    -   Q is selected from the group consisting of —OH, OR⁸,        NR^(c)R^(c), —NHR³⁹—C(O)R⁸, —NHR³⁹—C(O)OR⁸, —NR³⁹—CHR⁴⁰—R^(b),        —NR³⁹—(CH₂)_(m)—R^(b) and —NR³⁹—C(O)—CHR⁴⁰—NR^(c)R^(c);    -   R³⁹ and R⁴⁰ are each, independently of one another, selected        from the group consisting of hydrogen, alkyl, aryl, alkylaryl;        arylalkyl and NHR⁸; and    -   R^(a), R^(b) and R^(c) are as previously defined for structural        formula (I). Preferred R^(b) substitutents for Q are selected        from —C(O)OR⁸, —O—C(O)R⁸, —O—P(O)(OR⁸)₂ and —P(O)(OR⁸)₂.

In one embodiment of the above-depicted heteroaryls, as well as other5-15 membered heteroaryls according to this embodiment of the invention,each R⁸ is independently selected from the group consisting of R^(d),—NR^(c)R^(c), —(CH₂)_(m)—NR^(c)R^(c), —C(O)NR^(c)R^(c),—(CH₂)_(m)—C(O)NR^(c)R^(c), —C(O)OR^(d), —(CH₂)_(m)—C(O)OR^(d) and—(CH₂)_(m)—OR^(d), where m, R^(c) and R^(d) are as previously definedfor structural formula (I).

In a specific embodiment, R^(d) and/or R^(c) is selected from the groupconsisting of R^(a) and (C3-C8) cycloalkyl optionally substituted withone or more of the same or different hydroxyl, amino or carboxyl groups.

In another embodiment of the above-depicted heteroaryls, each R³⁵ ishydrogen or (C1-C6) ethyl or methyl.

In still another embodiment of the above-depicted heteroaryls, thearomatic ring connectivity is either at the 5 or 6 position. It shouldbe understood that either R² or R⁴ can utilize the heteroaryl groupsdiscussed throughout this specification.

In a fourteenth embodiment of the compounds of structural formulae (I)and (Ia), R² and R⁴ are each, independently of one another, anoptionally substituted phenyl, aryl or heteroaryl, with the provisosthat: (1) when L¹ is a direct bond and R⁶ and optionally R⁵ is hydrogen,then R² is other than 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6)alkoxyphenyl; (2) when L¹ and L² are each a direct bond, R⁶ is hydrogenand R⁵ is halo, then R² and R⁴ are not each simultaneously3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-C6) alkoxyphenyl; (3) when R⁴ is3-methoxyphenyl or 3-(C1-C6) alkoxyphenyl and R² is a3,4,5-trisubstituted phenyl, the substituents positioned at the 3 and 4positions are not both simultaneously methoxy or (C1-C6) alkoxy; (4)when R² is a substituted phenyl and R⁶ is hydrogen, then R⁵ is otherthan cyano or —C(O)NHR, where R is hydrogen or (C1-C6) alkyl; and/or (5)when R² and R⁴ are each independently a substituted or unsubstitutedpyrrole or indole, then the pyrrole or indole is attached to theremainder of the molecule via a ring carbon atom. Alternatively, R² issubject to the provisos described in connection with the first or secondembodiment.

In this fourteenth embodiment of the invention, the R² and R⁴substituents may be the same or different. Specific optionallysubstituted phenyl, aryl and/or heteroaryls include those illustratedabove in connection with the twelfth and thirteenth embodiments.

In a fifteenth embodiment of the compounds of structural formulae (I)and (Ia), including the above-described first through fourteenthembodiments thereof, R⁶ is hydrogen and R⁵ is an electronegative group.As will be recognized by skilled artisans, electronegative groups areatoms or groups of atoms that have a relatively great tendency toattract electrons to themselves. Specific examples of electronegativegroups according to this fourteenth embodiment include, but are notlimited to, —CN, —NC, —NO₂, halo, bromo, chloro, fluoro, (C1-C3)haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3)perfluoroalkyl, —CF₃, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, (C1-C3)fluoroalkoxy, (C1-C3) perfluoroalkoxy, —OCF₃, —C(O)R^(a), —C(O)OR^(a),—C(O)CF₃ and —C(O)OCF₃. In a specific embodiment, the electronegativegroup is a halogen-containing electronegative group, such as —OCF₃,—CF₃, bromo, chloro or fluoro. In another specific embodiment, R⁵ isfluoro, subject to the proviso that the the compound is not any compoundaccording to the third embodiment.

In a sixteenth embodiment, the compounds of structural formulae (I) and(Ia) are compounds according to structural formula (Ib):

and salts, hydrates, solvates and N-oxides thereof, wherein R¹¹, R¹²,R¹³ and R¹⁴ are each, independently of one another, selected from thegroup consisting of hydrogen, hydroxy, (C1-C6) alkoxy and —NR^(c)R^(c);and R⁵, R⁶ and R^(c) are as previously defined for structural formula(I), with the proviso that when R¹³, R⁵ and R⁶ are each hydrogen, thenR¹¹ and R¹² are not simultaneously methoxy, (C1-C6) alkoxy or (C1-C6)haloalkoxy

In a seventeenth embodiment, the compounds of structural formulae (I)and (Ia) are compounds according to structural formula (Ic):

and salts, hydrates, solvates and N-oxides thereof, wherein:

R⁴ is selected from the group consisting of 5-10 membered heteroaryl and3-hydroxyphenyl;

R⁵ is F or —CF₃; and

R⁸ is —O(CH₂)_(m)—R^(b), where m and R^(b) are as previously defined forstructural formula (I). In a specific embodiment, R⁸ is—O—CH₂—C(O)NH—CH₃ and/or R⁴ is a heteroaryl according to the thirteenthembodiment.

In an eighteenth embodiment, the compounds of structural formulae (I)and (Ia) include any compound selected from TABLE 1 that inhibits an Fcreceptor signal transduction cascade, a Syk kinase activity, aSyk-kinase dependent receptor signal transduction cascade orcelldegranulation as measured in an in vitro assay, optionally subject tothe proviso that the compound is not a compound excluded by theabove-described third embodiment and/or other embodiments. In a specificembodiment, such compounds have an IC₅₀ of about 20 μM or less asmeasured in an in vitro degranulation assay, such as one of thedegranulation assays described in the Examples section.

In a nineteenth embodiment, the compounds of structural formulae (I) and(Ia) include any compound selected from TABLE 1 that inhibits the FcγRIor FcεRI receptor cascade with an IC₅₀ of about 20 μM or less asmeasured in an in vitro assay, such as one of the in vitro assaysprovided in the Examples section, optionally subject to the proviso thatthe compound is not a compound excluded by the above-described thirdembodiment and/or other embodiments.

Also specifically described are combinations of the above first throughnineteenth specific embodiments.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the active 2,4-pyrimidinediaminecompounds described in TABLE 1, infra, include promoieties that arehydrolyzable or otherwise cleavable under conditions of use. Forexample, ester groups commonly undergo acid-catalyzed hydrolysis toyield the parent carboxylic acid when exposed to the acidic conditionsof the stomach, or base-catalyzed hydrolysis when exposed to the basicconditions of the intestine or blood. Thus, when administered to asubject orally, 2,4-pyrimidinediamines that include ester moieties maybe considered prodrugs of their corresponding carboxylic acid,regardless of whether the ester form is pharmacologically active.Referring to TABLE 1, numerous ester-containing 2,4-pyrimidinediaminesof the invention are active in their ester, “prodrug” form.

In the prodrugs of the invention, any available functional moiety may bemasked with a progroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that may be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, maybe included in the prodrugs of the invention.

In one illustrative embodiment, the prodrugs of the invention arecompounds according to structural formula (I) in which R^(c) and R^(d)may be, in addition to their previously-defined alternatives, aprogroup.

Replacing the hydrogens attached to N2 and N4 in the2,4-pyrimidinediamines of structural formula (I) with substituentsadversely effects the activity of the compounds. However, as will beappreciated by skilled artisans, these nitrogens may be included inpromoieties that, under conditions of use, cleave to yield2,4-pyrimidinediamines according to structural formula (I). Thus, inanother embodiment, the prodrugs of the invention are compoundsaccording to structural formula (II):

including salts, hydrates, solvates and N-oxides thereof, wherein:

R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined for structuralformula (I); and

R^(2b) and R^(4b) are each, independently of one another, a progroup.Specific examples of progroups according to this embodiment of theinvention include, but are not limited to, (C1-C6) alkyl, —C(O)CH₃,—C(O)NHR³⁶ and —S(O)₂R³⁶, where R³⁶ is (C1-C6) alkyl, (C5-C15) aryl and(C3-C8) cycloalkyl.

In the prodrugs of structural formula (II), the various substituents maybe as described for the various first through twentieth embodimentspreviously described for the compounds of structural formulae (I) and(Ia), or combinations of such embodiments.

Those of skill in the art will appreciate that many of the compounds andprodrugs of the invention, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pryimidinediamine core structure, atrop isomers are also possibleand are also specifically included in the compounds of the invention.

Moreover, skilled artisans will appreciate that when lists ofalternative substituents include members which, owing to valencyrequirements or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, skilled artisans will appreciate that while all ofthe listed alternatives for R^(b) can be used to substitute an alkylgroup, certain of the alternatives, such as ═O, cannot be used tosubstitute a phenyl group. It is to be understood that only possiblecombinations of substituent-group pairs are intended.

The compounds and/or prodrugs of the invention may be identified byeither their chemical structure or their chemical name. When thechemical structure and the chemical name conflict, the chemicalstructure is determinative of the identity of the specific compound.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention may be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts may be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydriodic, etc.), sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g. benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, etc.).

The 2,4-pyrimidinediamine compounds and of the invention, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

6.3 Methods of Synthesis

The compounds and prodrugs of the invention may be synthesized via avariety of different synthetic routes using commercially availablestarting materials and/or starting materials prepared by conventionalsynthetic methods. Suitable exemplary methods that may be routinelyadapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugsof the invention are found in U.S. Pat. No. 5,958,935, the disclosure ofwhich is incorporated herein by reference. Specific examples describingthe synthesis of numerous compounds and prodrugs of the invention, aswell as intermediates therefor, are provided in the Examples section.All of the compounds of structural formulae (I), (Ia) and (II) may beprepared by routine adaptation of these methods.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(XI), below. In Schemes (I)-(XI), like-numbered compoundshave similar structures. These methods may be routinely adapted tosynthesize the prodrugs according to structural formula (II).

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils or thiouracils as illustrated inScheme (I), below:

In Scheme (I), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forstructural formula (I), X is a halogen (e.g., F, Cl, Br or I) and Y andY′ are each, independently of one another, selected from the groupconsisting of O and S. Referring to Scheme (I), uracil or thiouracil 2is dihalogenated at the 2- and 4-positions using standard halogenatingagent POX₃ (or other standard halogenating agent) under standardconditions to yield 2,4-bishalo pyrimidine 4. Depending upon the R⁵substituent, in pyrimidine 4, the halide at the C4 position is morereactive towards nucleophiles than the halide at the C2 position. Thisdifferential reactivity can be exploited to synthesize2,4-pyrimidinediamines according structural formula (I) by firstreacting 2,4-bishalopyrimidine 4 with one equivalent of amine 10,yielding 4N-substituted-2-halo-4-pyrimidineamine 8, followed by amine 6to yield a 2,4-pyrimidinediamine according structural formula (I).2N,4N-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtainedby reacting 2,4-bishalopyrimidine 4 with excess 6 or 10, respectively.

In most situations, the C4 halide is more reactive towards nucleophiles,as illustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the R⁵ substituent may alter this reactivity.For example, when R⁵ is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine 8 and the corresponding2N-substituted-2-pyrimidineamine is obtained. Regardless of the identityof the R⁵ substituent, the regioselectivity of the reaction can becontrolled by adjusting the solvent and other synthetic conditions (suchas temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions may be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry) in asealed tube (at 20 bar pressure).

The uracil or thiouracil 2 starting materials may be purchased fromcommercial sources or prepared using standard techniques of organicchemistry. Commercially available uracils and thiouracils that can beused as starting materials in Scheme (I) include, by way of example andnot limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8);2-thio-uracil (Aldrich #11,558-4; CAS Registry 141-90-2);2,4-dithiouracil (Aldrich #15,846-1; CAS Registry 2001-93-6);5-acetouracil (Chem. Sources Int'l 2000; CAS Registry 6214-65-9);5-azidouracil; 5-aminouracil (Aldrich #85,528-6; CAS Registry 932-52-5);5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7);5-(trans-2-bromovinyl)-uracil (Aldrich #45,744-2; CAS Registry69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CAS Registry 81751-48-2);5-(trans-2-carboxyvinyl)-uracil; uracil-5-carboxylic acid(2,4-dihydroxypyrimidine-5-carboxylic acid hydrate; Aldrich #27,770-3;CAS Registry 23945-44-0); 5-chlorouracil (Aldrich #22,458-8; CASRegistry 1820-81-1); 5-cyanouracil (Chem. Sources Int'l 2000; CASRegistry 4425-56-3); 5-ethyluracil (Aldrich #23,044-8; CAS Registry4212-49-1); 5-ethenyluracil (CAS Registry 37107-81-6); 5-fluorouracil(Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich#85,785-8; CAS Registry 696-07-1); 5-methyluracil (thymine; Aldrich#13,199-7; CAS Registry 65-71-4); 5-nitrouracil (Aldrich #85,276-7; CASRegistry 611-08-5); uracil-5-sulfamic acid (Chem. Sources Int'l 2000;CAS Registry 5435-16-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1;CAS Registry 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CAS Registry155143-31-6); 5-(pentafluoroethyl)-uracil (CAS Registry 60007-38-3);6-aminouracil (Aldrich #A5060-6; CAS Registry 873-83-6)uracil-6-carboxylic acid (orotic acid; Aldrich #0-840-2; CAS Registry50887-69-9); 6-methyluracil (Aldrich #D 11,520-7; CAS Registry626-48-2); uracil-5-amino-6-carboxylic acid (5-aminoorotic acid; Aldrich#19,121-3; CAS Registry #7164-43-4); 6-amino-5-nitrosouracil(6-amino-2,4-dihydroxy-5-nitrosopyrimidine; Aldrich #27,689-8; CASRegistry 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluorooroticacid; Aldrich #42,513-3; CAS Registry 00000-00-0); anduracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; Aldrich #18,528-0;CAS Registry 600779-49-9). Additional 5-, 6- and 5,6-substituted uracilsand/or thiouracils are available from General Intermediates of Canada,Inc., Edmonton, Calif. (www.generalintermediates.com) and/or Interchim,Cedex, France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Amines 6 and 10 may be purchased from commercial sources or,alternatively, may be synthesized utilizing standard techniques. Forexample, suitable amines may be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines 6 and 10and/or substituents R⁵ and/or R⁶ on uracil or thiouracil 2 may includefunctional groups that require protection during synthesis. The exactidentity of any protecting group(s) used will depend upon the identityof the functional group being protected, and will be apparent to theseof skill in the art. Guidance for selecting appropriate protectinggroups, as well as synthetic strategies for their attachment andremoval, may be found, for example, in Greene & Wuts, Protective Groupsin Organic Synthesis, 3d Edition, John Wiley & Sons, Inc., New York(1999) and the references cited therein (hereinafter “Greene & Wuts”).

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32,937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), R², R⁴, L¹ and L² are as previously defined for Scheme(I). According to Scheme (Ia), 5-fluorouracil 3 is halogenated withPOCl₃ to yield 2,4-dichloro-5-fluoropyrimidine 5, which is then reactedwith excess amine 6 or 10 to yield N2,N4-bis substituted5-fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively,asymmetric 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine 9 may beobtained by reacting 2,4-dichloro-5-fluoropyrimidine 5 with oneequivalent of amine 10 (to yield2-chloro-N-4-substituted-5-fluoro-4-pyrimidineamine 7) followed by oneor more equivalents of amine 6.

In another exemplary embodiment, the 2,4-pyrimidinediamine compounds ofthe invention may be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (IIa) and (IIb), R², R⁴, R⁵, R⁶, L¹, L² and X are aspreviously defined for Scheme (I) and PG represents a protecting group.Referring to Scheme (IIa), the C4 exocyclic amine of cytosine 20 isfirst protected with a suitable protecting group PG to yieldN4-protected cytosine 22. For specific guidance regarding protectinggroups useful in this context, see Vorbruggen and Ruh-Pohlenz, 2001,Handbook of Nucleoside Synthesis, John Wiley & Sons, NY, pp. 1-631(“Vorbrüggen”). Protected cytosine 22 is halogenated at the C2 positionusing a standard halogenation reagent under standard conditions to yield2-chloro-4N-protected-4-pyrimidineamine 24. Reaction with amine 6followed by deprotection of the C4 exocyclic amine and reaction withamine 10 yields a 2,4-pyrimidinediamine according to structural formula(I).

Alternatively, referring to Scheme (IIb), cytosine 20 may be reactedwith amine 10 or protected amine 21 to yield N4-substituted cytosine 23or 27, respectively. These substituted cytosines may then be halogenatedas previously described, deprotected (in the case of N4-substitutedcytosine 27) and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Commercially-available cytosines that may be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14,201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37,791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich#27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine.Other suitable cytosines useful as starting materials in Schemes (IIa)are available from General Intermediates of Canada, Inc., Edmonton,Calif. (www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention may be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and Z is a leaving group as discussed in more detail inconnection with Scheme IV, infra. Referring to Scheme (III),2-amino-4-pyrimidinol 30 is reacted with amine 6 (or optionallyprotected amine 21) to yield N2-substituted-4-pyrimidinol 32, which isthen halogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineanine 34. Optional deprotection (forexample if protected amine 21 was used in the first step) followed byreaction with amine 10 affords a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, pyrimidinol 30 can be reactedwith acylating agent 31.

Suitable commercially-available 2-amino-4-pyrimidinols 30 that can beused as starting materials in Scheme (III) include, but are not limitedto, 2-amino-6-chloro-4-pyrimidinol hydrate (Aldrich #A4702-8; CASRegistry 00000-00-0) and 2-amino-6-hydroxy-4-pyrimidinol (Aldrich#A5040-1; CAS Registry 56-09-7). Other 2-amino-4-pyrimidinols 30 usefulas starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif.(www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention maybe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), R², R⁴, R⁵, R⁶, L¹ and L² are as previously defined forScheme (I) and Z represents a leaving group. Referring to Scheme (IV),the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine 6 yieldsN2-substituted-2,4-pyrimidinediamine 42. Subsequent reaction withcompound 44, which includes a good leaving group Z, or amine 10 yields a2,4-pyrimidinediamine according to structural formula (I). Compound 44may include virtually any leaving group that can be displaced by theC4-amino of N2-substituted-2,4-pyrimidinediamine 42. Suitable leavinggroups Z include, but are not limited to, halogens, methanesulfonyloxy(mesyloxy; “OMs”), trifluoromethanesulfonyloxy (“OTf”) andp-toluenesulfonyloxy (tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”)and metanitro benzene sulfonyloxy (“nosylate”). Other suitable leavinggroups will be apparent to those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials may be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), R², R⁴, R⁵, R⁶, L¹, L² and X are as defined for Scheme(I) and Z is as defined for Scheme (IV). Referring to Scheme (V),2-amino-4-chloropyrimidine 50 is reacted with amino 10 to yield4N-substituted-2-pyrimidineamine 52 which, following reaction withcompound 31 or amine 6, yields a 2,4-pyrimidinediamine according tostructural formula (I). Alternatively, 2-chloro-4-amino-pyrimidine 54may be reacted with compound 44 followed by amine 6 to yield a compoundaccording to structural formula (I).

A variety of pyrimidines 50 and 54 suitable for use as startingmaterials in Scheme (V) are commercially available, including by way ofexample and not limitation, 2-amino-4,6-dichloropyrimidine (Aldrich#A4860-1; CAS Registry 56-05-3); 2-amino-4-chloro-6-methoxy-pyrimidine(Aldrich #51,864-6; CAS Registry 5734-64-5);2-amino-4-chloro-6-methylpyrimidine (Aldrich #12,288-2; CAS Registry5600-21-5); and 2-amino-4-chloro-6-methylthiopyrimidine (Aldrich#A4600-5; CAS Registry 1005-38-5). Additional pyrimidine startingmaterials are available from General Intermediates of Canada, Inc.,Edmonton, Calif. (www.generalintermediates.com) and/or Interchim, Cedex,France (www.interchim.com), or may be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

Alternatively, 4-chloro-2-pyrimidineamines 50 may be prepared asillustrated in Scheme (Va):

In Scheme (Va), R⁵ and R⁶ are as previously defined for structuralformula (I). In Scheme (Va), dicarbonyl 53 is reacted with guanidine toyield 2-pyrimidineamine 51. Reaction with peracids likem-chloroperbenzoic acid, trifluoroperacetic acid or urea hydrogenperoxide complex yields N-oxide 55, which is then halogenated to give4-chloro-2-pyrimidineamine 50. The corresponding4-halo-2-pyrimidineamines may be obtained by using suitable halogenationreagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedfor Scheme (I) and the superscript PG represents a protecting group, asdiscussed in connection with Scheme (IIb). According to Scheme (VI),uridine 60 has a C4 reactive center such that reaction with amine 10 orprotected amine 21 yields N4-substituted cytidine 62 or 64,respectively. Acid-catalyzed deprotection of N4-substituted 62 or 64(when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine 28, which may be subsequently halogenated at theC2-position and reacted with amine 6 to yield a 2,4-pyrimidinediamineaccording to structural formula (I).

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), R², R⁴, R⁵, R⁶, L¹, L² and X are as previously definedin Scheme (I) and the superscript PG represents a protecting group asdiscussed above. Referring to Scheme (VII), like uridine 60, cytidine 70has a C4 reactive center such that reaction with amine 10 or protectedamine 21 yields N4-substituted cytidine 62 or 64, respectively. Thesecytidines 62 and 64 are then treated as previously described for Scheme(VI) to yield a 2,4-pyrimidinediamine according to structural formula(I).

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66,384-66-5); 5-bromouridine (Chem. Sources Int'l2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32,937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85,259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000;CAS Registry 70-00-8). Additional uridines and cytidines that can beused as starting materials in Schemes (VI) and (VII) are available fromGeneral Intermediates of Canada, Inc., Edmonton, Calif.(www.generalintermediates.com) and/or Interchim, Cedex, France(www.interchim.com), or may be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

The 2,4-pyrimidinediamine compounds of the invention can also besynthesized from substituted pyrimidines, such as chloro-substitutedpyrimidines, as illustrated in Schemes (VIII) and (IX), below:

In Schemes (VIII) and (IX), R², R⁴, L¹, L² and R^(a) are as previouslydefined for structural formula (I) and “Ar” represents an aryl group.Referring to Scheme (VIII), reaction of 2,4,6-trichloropyrimidine 80(Aldrich #T5,620-0; CAS#3764-01-0) with amine 6 yields a mixture ofthree compounds: substituted pyrimidine mono-, di- and triamines 81, 82and 83, which can be separated and isolated using HPLC or otherconventional techniques. Mono- and diamines 81 and 82 may be furtherreacted with amines 6 and/or 10 to yieldN2,N4,N6-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85,respectively.

N2,N4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manneranalogous to Scheme (VIII) by employing 2,4-dichloro-5-methylpyrimidineor 2,4-dichloro-pyrimidine as starting materials. In this instance, themono-substituted pyrimidineamine corresponding to compound 81 is notobtained. Instead, the reaction proceeds to yield theN2,N4-bis-substituted-2,4-pyrimidinediamine directly.

Referring to Scheme (IX), 2,4,5,6-tetrachloropyrimidine 90 (Aldrich#24,671-9; CAS#1780-40-1) is reacted with excess amine 6 to yield amixture of three compounds: 91, 92, and 93, which can be separated andisolated using HPLC or other conventional techniques. As illustrated,N2,N4-bis-substituted-5,6,-dichloro-2,4-pyrimidinediamine 92 may befurther reacted at the C6 halide with, for example a nucleophilic agent94 to yield compound 95. Alternatively, compound 92 can be convertedinto N2,N4-bis-subsituted-5-chloro-6-aryl-2,4-pyrimidinediamine 97 via aSuzuki reaction. 2,4-Pyrimidinediamine 95 may be converted to2,4-pyrimidinediamine 99 by reaction with Bn₃SnH.

As will be recognized by skilled artisans, 2,4-pyrimidinediaminesaccording to the invention, synthesized via the exemplary methodsdescribed above or by other well-known means, may also be utilized asstarting materials and/or intermediates to synthesize additional2,4-pyrimidinediamine compounds of the invention. A specific example isillustrated in Scheme (X), below:

In Scheme (X), R⁴, R⁵, R⁶, L² and R^(a) are as previously defined forstructural formula (I). Each R^(a′) is independently an R^(a), and maybe the same or different from the illustrated R^(a). Referring to Scheme(X), carboxylic acid or ester 100 may be converted to amide 104 byreaction with amine 102. In amine 102, R^(a′) may be the same ordifferent than R^(a) of acid or ester 100. Similarly, carbonate ester106 may be converted to carbamate 108.

A second specific example is illustrated in Scheme (XI), below:

In Scheme (XI), R⁴, R⁵, R⁶, L² and R^(c) are as previously defined forstructural formula (I). Referring to Scheme (XI), amide 110 or 116 maybe converted to amine 114 or 118, respectively, by borane reduction withborane methylsulfide complex 112. Other suitable reactions forsynthesizing 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediaminestarting materials will be apparent to those of skill in the art.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances substituents R², R⁴, R⁵, R⁶, L¹ and/or L² may includefunctional groups requiring protection. The exact identity of theprotecting group used will depend upon, among other things, the identityof the functional group being protected and the reaction conditions usedin the particular synthetic scheme, and will be apparent to those ofskill in the art. Guidance for selecting protecting groups andchemistries for their attachment and removal suitable for a particularapplication can be found, for example, in Greene & Wuts, supra.

Prodrugs according to structural formula (II) may be prepared by routinemodification of the above-described methods. Alternatively, suchprodrugs may be prepared by reacting a suitably protected2,4-pyrimidinediamine of structural formula (I) with a suitableprogroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrug of formula (II) arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(IX),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidine synthesis pp. 313-316; aminopyrimidine synthesis pp. 315); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall, London,UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

6.4 Inhibition of Fc Receptor Signal Cascades

Active 2,4-pyrimidinediamine compounds of the invention inhibit Fcreceptor signalling cascades that lead to, among other things,degranulation of cells. As a specific example, the compounds inhibit theFcεRI and/or FcγRI signal cascades that lead to degranulation of immunecells such as neutrophil, eosinophil, mast and/or basophil cells. Bothmast and basophil cells play a central role in allergen-induceddisorders, including, for example, allergic rhinitis and asthma.Referring to FIG. 1, upon exposure allergens, which may be, among otherthings, pollen or parasites, allergen-specific IgE antibodies aresynthesized by B-cells activated by IL-4 (or IL-13) and other messengersto switch to IgE class specific antibody synthesis. Theseallergen-specific IgEs bind to the high affinity FcεRI. Upon binding ofantigen, the FcεRI-bound IgEs are cross-linked and the IgE receptorsignal transduction pathway is activated, which leads to degranulationof the cells and consequent release and/or synthesis of a host ofchemical mediators, including histamine, proteases (e.g., tryptase andchymase), lipid mediators such as leukotrienes (e.g., LTC4),platelet-activating factor (PAF) and prostaglandins (e.g., PGD2) and aseries of cytokines, including TNF-α, IL-4, IL-13, IL-5, IL-6, IL-8,GMCSF, VEGF and TGF-β. The release and/or synthesis of these mediatorsfrom mast and/or basophil cells accounts for the early and late stageresponses induced by allergens, and is directly linked to downstreamevents that lead to a sustained inflammatory state.

The molecular events in the FcεRI signal transduction pathway that leadto release of preformed mediators via degranulation and release and/orsynthesis of other chemical mediators are well-known and are illustratedin FIG. 2. Referring to FIG. 2, the FcεRI is a heterotetrameric receptorcomposed of an IgE-binding alpha-subunit, a beta subunit, and two gammasubunits (gamma homodimer). Cross-linking of FcεRI-bound IgE bymultivalent binding agents (including, for example IgE-specificallergens or anti-IgE antibodies or fragments) induces the rapidassociation and activation of the Src-related kinase Lyn. Lynphosphorylates immunoreceptor tyrosine-based activation motifs (ITAMS)on the intracellular beta and gamma subunits, which leads to therecruitment of additional Lyn to the beta subunit and Syk kinase to thegamma homodimer. These receptor-associated kinases, which are activatedby intra- and intermolecular phosphorylation, phosphorylate othercomponents of the pathway, such as the Btk kinase, LAT, andphospholipase C-gamma PLC-gamma). Activated PLC-gamma initiates pathwaysthat lead to protein kinase C activation and Ca²⁺ mobilization, both ofwhich are required for degranulation. FcεRI cross-linking also activatesthe three major classes of mitogen activated protein (MAP) kinases, i.e.ERK1/2, JNK1/2, and p38. Activation of these pathways is important inthe transcriptional regulation of proinflammatory mediators, such asTNF-α and IL-6, as well as the lipid mediator leukotriene CA (LTC4).

Although not illustrated, the FcγRI signaling cascade is believed toshare some common elements with the FceRI signaling cascade.Importantly, like FcεRI, the FcγRI includes a gamma homodimer that isphosphorylated and recruits Syk, and like FcεRI, activation of the FcγRIsignaling cascade leads to, among other things, degranulation. Other Fcreceptors that share the gamma homodimer, and which can be regulated bythe active 2,4-pyrimidinediamine compounds include, but are not limitedto, FcαRI and FcεRIII.

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit Fc receptor signaling cascades may be simply determined orconfirmed in in vitro assays. Suitable assays for confirming inhibitionof FcεRI-mediated degranulation are provided in the Examples section. Inone typical assay, cells capable of undergoing FcεRI-mediateddegranulation, such as mast or basophil cells, are first grown in thepresence of IL-4, Stem Cell Factor (SCF), IL-6 and IgE to increaseexpression of the FcεRI, exposed to a 2,4-pyrimidinediamine testcompound of the invention and stimulated with anti-IgE antibodies (or,alternatively, an IgE-specific allergen). Following incubation, theamount of a chemical mediator or other chemical agent released and/orsynthesized as a consequence of activating the FcεRI signaling cascademay be quantified using standard techniques and compared to the amountof the mediator or agent released from control cells (i.e., cells thatare stimulated but that are not exposed to test compound). Theconcentration of test compound that yields a 50% reduction in thequantity of the mediator or agent measured as compared to control cellsis the IC₅₀ of the test compound. The origin of the mast or basophilcells used in the assay will depend, in part, on the desired use for thecompounds and will be apparent to those of skill in the art. Forexample, if the compounds will be used to treat or prevent a particulardisease in humans, a convenient source of mast or basophil cells is ahuman or other animal which constitutes an accepted or known clinicalmodel for the particular disease. Thus, depending upon the particularapplication, the mast or basophil cells may be derived from a widevariety of animal sources, ranging from, for example, lower mammals suchas mice and rats, to dogs, sheep and other mammals commonly employed inclinical testing, to higher mammals such as monkeys, chimpanzees andapes, to humans. Specific examples of cells suitable for carrying outthe in vitro assays include, but are not limited to, rodent or humanbasophil cells, rat basophil leukemia cell lines, primary mouse mastcells (such as bone marrow-derived mouse mast cells “BMMC”) and primaryhuman mast cells isolated from cord blood (“CHMC”) or other tissues suchas lung. Methods for isolating and culturing these cell types arewell-known or are provided in the Examples section (see, e.g., Demo etal., 1999, Cytometry 36(4):340-348 and copending application Ser. No.10/053,355, filed Nov. 8, 2001, the disclosures of which areincorporated herein by reference). Of course, other types of immunecells that degranulate upon activation of the FcεRI signaling cascademay also be used, including, for example, eosinophils.

As will be recognized by skilled artisans, the mediator or agentquantified is not critical. The only requirement is that it be amediator or agent released and/or synthesized as a consequence ofinitiating or activating the Fc receptor signaling cascade. For example,referring to FIG. 1, activation of the FcεRI signaling cascade in mastand/or basophil cells leads to numerous downstream events. For example,activation of the FcεRI signal cascade leads to the immediate release(i.e., within 1-3 min. following receptor activation) of a variety ofpreformed chemical mediators and agents via degranulation. Thus, in oneembodiment, the mediator or agent quantified may be specific to granules(i.e., present in granules but not in the cell cytoplasm generally).Examples of granule-specific mediators or agents that can be quantifiedto determine and/or confirm the activity of a 2,4-pyrimidinediaminecompound of the invention include, but are not limited to,granule-specific enzymes such as hexosaminidase and tryptase andgranule-specific components such as histamine and serotonin. Assays forquantifying such factors are well-known, and in many instances arecommercially available. For example, tryptase and/or hexosaminidaserelease may be quantified by incubating the cells with cleavablesubstrates that fluoresce upon cleavage and quantifying the amount offluorescence produced using conventional techniques. Such cleavablefluorogenic substrates are commercially available. For example, thefluorogenic substrates Z-Gly-Pro-Arg-AMC (Z=benzyloxycarbonyl;AMC=7-amino-4-methylcoumarin; BIOMOL Research Laboratories, Inc.,Plymouth Meeting, Pa. 19462, Catalog No. P-142) and Z-Ala-Lys-Arg-AMC(Enzyme Systems Products, a division of ICN Biomedicals, Inc.,Livermore, Calif. 94550, Catalog No. AMC-246) can be used to quantifythe amount of tryptase released. The fluorogenic substrate4-methylumbelliferyl-N-acetyl-β-D-glucosaminide (Sigma, St. Louis, Mo.,Catalog #69585) can be used to quantify the amount of hexosaminidasereleased. Histamine release may be quantified using a commerciallyavailable enzyme-linked immunosorbent assay (ELISA) such as Immunotechhistamine ELISA assay #IM2015 (Beckman-Coulter, Inc.). Specific methodsof quantifying the release of tryptase, hexosaminidase and histamine areprovided in the Examples section. Any of these assays may be used todetermine or confirm the activity of the 2,4-pyrimidinediamine compoundsof the invention.

Referring again to FIG. 1, degranulation is only one of severalresponses initiated by the FcεRI signaling cascade. In addition,activation of this signaling pathway leads to the de novo synthesis andrelease of cytokines and chemokines such as IL-4, IL-5, IL-6, TNF-α,IL-13 and MIP1-α), and release of lipid mediators such as leukotrienes(e.g., LTC4), platelet activating factor (PAF) and prostaglandins.Accordingly, the 2,4-pyrimidinediamine compounds of the invention mayalso be assessed for activity by quantifying the amount of one or moreof these mediators released and/or synthesized by activated cells.

Unlike the granule-specific components discussed above, these “latestage” mediators are not released immediately following activation ofthe FcεRI signaling cascade. Accordingly, when quantifying these latestage mediators, care should be taken to insure that the activated cellculture is incubated for a time sufficient to result in the synthesis(if necessary) and release of the mediator being quantified. Generally,PAF and lipid mediators such as leukotriene C4 are released 3-30 min.following FcεRI activation. The cytokines and other late stage mediatorsare released approx. 4-8 hrs. following FcεRI activation. Incubationtimes suitable for a specific mediator will be apparent to those ofskill in the art. Specific guidance and assays are provided in theExamples section.

The amount of a particular late stage mediator released may bequantified using any standard technique. In one embodiment, theamount(s) may be quantified using ELISA assays. ELISA assay kitssuitable for quantifying the amount of TNFα, IL-4, IL-5, IL-6 and/orIL-13 released are available from, for example, Biosource International,Inc., Camarillo, Calif. 93012 (see, e.g., Catalog Nos. KHC3011, KHC0042,KHC0052, KHC0061 and KHC0132). ELISA assay kits suitable for quantifyingthe amount of leukotriene C4 (LTC4) released from cells are availablefrom Cayman Chemical Co., Ann Arbor, Mich. 48108 (see, e.g., Catalog No.520211).

Typically, active 2,4-pyrimidinediamine compounds of the invention willexhibit IC₅₀s with respect to FcεRI-mediated degranulation and/ormediator release or synthesis of about 20 μM or lower, as measured in anin vitro assay, such as one of the in vitro assays described above or inthe Examples section. Of course, skilled artisans will appreciate thatcompounds which exhibit lower IC₅₀s, for example on the order of 10 μM,1 μM, 100 nM, 10 nM, 1 nM, or even lower, are particularly useful.

Skilled artisans will also appreciate that the various mediatorsdiscussed above may induce different adverse effects or exhibitdifferent potencies with respect to the same adverse effect. Forexample, the lipid mediator LTC4 is a potent vasoconstrictor—it isapproximately 1000-fold more potent at inducing vasoconstriction thanhistamine. As another example, in addition to mediating atopic or Type Ihypersensitivity reactions, cytokines can also cause tissue remodelingand cell proliferation. Thus, although compounds that inhibit releaseand/or synthesis of any one of the previously discussed chemicalmediators are useful, skilled artisans will appreciate that compoundswhich inhibit the release and/or synthesis of a plurality, or even all,of the previously described mediators find particular use, as suchcompounds are useful for ameliorating or avoiding altogether aplurality, or even all, of the adverse effects induced by the particularmediators. For example, compounds which inhibit the release of all threetypes of mediators—granule-specific, lipid and cytokine—are useful fortreating or preventing immediate Type I hypersensitivity reactions aswell as the chronic symptoms associated therewith.

Compounds of the invention capable of inhibiting the release of morethan one type of mediator (e.g., granule-specific or late stage) may beidentified by determining the IC₅₀ with respect to a mediatorrepresentative of each class using the various in vitro assays describedabove (or other equivalent in vitro assays). Compounds of the inventionwhich are capable of inhibiting the release of more than one mediatortype will typically exhibit an IC₅₀ for each mediator type tested ofless than about 20 μM. For example, a compound which exhibits an IC₅₀ of1 μM with respect to histamine release (IC₅₀ ^(histamine)) and anIC_(50 of) 1 nM with respect to leukotriene LTC4 synthesis and/orrelease (IC₅₀ ^(LTC4)) inhibits both immediate (granule-specific) andlate stage mediator release. As another specific example, a compoundthat exhibits an IC₅₀ ^(tryptase) of 10 μM, an IC₅₀ ^(LTC4) of 1 μM andan IC₅₀ ^(IL-4) of 1 μM inhibits immediate (granule-specific), lipid andcytokine mediator release. Although the above specific examples utilizethe IC₅₀s of one representative mediator of each class, skilled artisanswill appreciate that the IC₅₀s of a plurality, or even all, mediatorscomprising one or more of the classes may be obtained. The quantity(ies)and identity(ies) of mediators for which IC₅₀ data should be ascertainedfor a particular compound and application will be apparent to those ofskill in the art.

Similar assays may be utilized to confirm inhibition of signaltransduction cascades initiated by other Fc receptors, such as FcαRI,FcγRI and/or FcγRIII signaling, with routine modification. For example,the ability of the compounds to inhibit FcγRI signal transduction may beconfirmed in assays similar to those described above, with the exceptionthat the FcγRI signaling cascade is activated, for example by incubatingthe cells with IgG and an IgG-specific allergen or antibody, instead ofIgE and an IgE-specific allergen or antibody. Suitable cell types,activating agents and agents to quantify to confirm inhibition of otherFc receptors, such as Fc receptors that comprise a gamma homodimer, willbe apparent to those of skill in the art.

One particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators and late stage mediators with approximatelyequivalent IC₅₀s. By approximately equivalent is meant that the IC₅₀sfor each mediator type are within about a 10-fold range of one another.Another particularly useful class of compounds includes those2,4-pyrimidinediamine compounds that inhibit the release of immediategranule-specific mediators, lipid mediators and cytokine mediators withapproximately equivalent IC₅₀s. In a specific embodiment, such compoundsinhibit the release of the following mediators with approximatelyequivalent IC₅₀s: histamine, tryptase, hexosaminidase, IL-4, IL-5, IL-6,IL-13, TNFα and LTC4. Such compounds are particularly useful for, amongother things, ameliorating or avoiding altogether both the early andlate stage responses associated with atopic or immediate Type Ihypersensitivity reactions.

Ideally, the ability to inhibit the release of all desired types ofmediators will reside in a single compound. However, mixtures ofcompounds can also be identified that achieve the same result. Forexample, a first compound which inhibits the release of granule specificmediators may be used in combination with a second compound whichinhibits the release and/or synthesis of cytokine mediators.

In addition to the FcεRI or FcγRI degranulation pathways discussedabove, degranulation of mast and/or basophil cells can be induced byother agents. For example, ionomycin, a calcium ionophore that bypassesthe early FcεRI or FcγRI signal transduction machinery of the cell,directly induces a calcium flux that triggers degranulation. Referringagain to FIG. 2, activated PLCγ initiates pathways that lead to, amongother things, calcium ion mobilization and subsequent degranulation. Asillustrated, this Ca²⁺ mobilization is triggered late in the FcεRIsignal transduction pathway. As mentioned above, and as illustrated inFIG. 3, ionomycin directly induces Ca²⁺ mobilization and a Ca²⁺ fluxthat leads to degranulation. Other ionophores that induce degranulationin this manner include A23187. The ability of granulation-inducingionophores such as ionomycin to bypass the early stages of the FcεRIand/or FcγRI signaling cascades may be used as a counter screen toidentify active compounds of the invention that specifically exert theirdegranulation-inhibitory activity by blocking or inhibiting the earlyFcεRI or FcγRI signaling cascades, as discussed above. Compounds whichspecifically inhibit such early FcεRI or FcγRI-mediated degranulationinhibit not only degranulation and subsequent rapid release ofhistamine, tryptase and other granule contents, but also inhibit thepro-inflammatory activation pathways causing the release of TNFα, IL-4,IL-13 and the lipid mediators such as LTC4. Thus, compounds whichspecifically inhibit such early FcεRI and/or FcγRI-mediateddegranulation block or inhibit not only acute atopic or Type Ihypersensitivity reactions, but also late responses involving multipleinflammatory mediators.

Compounds of the invention that specifically inhibit early FcεRI and/orFcγRI-mediated degranulation are those compounds that inhibit FcεRIand/or FcγRI-mediated degranulation (for example, have an IC₅₀ of lessthan about 20 μM with respect to the release of a granule-specificmediator or component as measured in an in vitro assay with cellsstimulated with an IgE or IgG binding agent) but that do not appreciablyinhibit ionophore-induced degranulation. In one embodiment, compoundsare considered to not appreciably inhibit ionophore-induceddegranulation if they exhibit an IC₅₀ of ionophore-induced degranulationof greater than about 20 μM, as measured in an in vitro assay. Ofcourse, active compounds that exhibit even higher IC₅₀s ofionophore-induced degranulation, or that do not inhibitionophore-induced degranulation at all, are particularly useful. Inanother embodiment, compounds are considered to not appreciably inhibitionophore-induced degranulation if they exhibit a greater than 10-folddifference in their IC₅₀s of FcεRI and/or FcγRI-mediated degranulationand ionophore-induced degranulation, as measured in an in vitro assay.Assays suitable for determining the IC₅₀ of ionophore-induceddegranulation include any of the previously-described degranulationassays, with the modification that the cells are stimulated or activatedwith a degranulation-inducing calcium ionophore such as ionomycin orA23187 (A.G. Scientific, San Diego, Calif.) instead of anti-IgEantibodies or an IgE-specific allergen. Specific assays for assessingthe ability of a particular 2,4-pyrimidinediamine compound of theinvention to inhibit ionophore-induced degranulation are provided in theExamples section.

As will be recognized by skilled artisans, compounds which exhibit ahigh degree of selectivity of FcεRI-mediated degranulation findparticular use, as such compounds selectively target the FcεRI cascadeand do not interfere with other degranulation mechanisms. Similarly,compounds which exhibit a high degree of selectivity of FcγRI-mediateddegranulation find particular use, as such compounds selectively targetthe FcγRI cascade and do not interfere with other degranulationmechanisms. Compounds which exhibit a high degree of selectivity aregenerally 10-fold or more selective for FcεRI- or FcγRI-mediateddegranulation over ionophore-induced degranulation, such asionomycin-induced degranulation.

Biochemical and other data confirm that the 2,4-pyrimidinediaminecompounds described herein are potent inhibitors of Syk kinase activity.For example, in experiments with an isolated Syk kinase, of twenty four2,4-pyrimidinediamine compounds tested, all but two inhibited the Sykkinase catalyzed phosphorylation of a peptide substrate with IC50s inthe submicromolar range. The remaining compounds inhibitedphosphorylation in the micromolar range. In addition, of sixteencompounds tested in an in vitro assay with mast cells, all inhibitedphosphorylation of Syk kinase substrates (e.g., PLC-gammal, LAT) andproteins downstream of Syk kinase (e.g., JNK, p38, Erk1/2 and PKB, whentested), but not proteins upstream of Syk kinase in the cascade (e.g.,Lyn). Phosphorylation of Lyn substrates was not inhibited by the2,4-pyrimidinediamine compounds tested. Moreover, for the followingcompounds, a high correlation was observed between their inhibition ofSyk kinase activity in biochemical assays (IC₅₀s in the range of 3 to1850 nM) and their inhibition of FcεRI-mediated degranulation in mastcells (IC₅₀s in the range of 30 to 1650 nM): R950373, R950368, R921302,R945371, R945370, R945369, R945365, R921304, R945144, R945140, R945071,R940358, R940353, R940352, R940351, R940350, R940347, R921303, R940338,R940323, R940290, R940277, R940276, R940275, R940269, R940255, R935393,R935372, R935366, R935310, R935309, R935307, R935304, R935302, R935293,R935237, R935198, R935196, R935194, R935193, R935191, R935190, R935138,R927050, R926968, R926956, R926931, R926891, R926839, R926834, R926816,R926813, R926791, R926782, R926780, R926757, R926753, R926745, R926715,R926508, R926505, R926502, R926501, R926500, R921218, R921147, R920410,R909268, R921219, R908712, R908702.

Accordingly, the activity of the 2,4-pyrimidinediamine compounds of theinvention may also be confirmed in biochemical or cellular assays of Sykkinase activity. Referring again to FIG. 2, in the FcεRI signalingcascade in mast and/or basophil cells, Syk kinase phosphorylates LAT andPLC-gammal, which leads to, among other things, degranulation. Any ofthese activities may be used to confirm the activity of the2,4-pyrimidinediamine compounds of the invention. In one embodiment, theactivity is confirmed by contacting an isolated Syk kinase, or an activefragment thereof with a 2,4-pyrimidinediamine compound in the presenceof a Syk kinase substrate (e.g., a synthetic peptide or a protein thatis known to be phophorylated by Syk in a signaling cascade) andassessing whether the Syk kinase phosphorylated the substrate.Alternatively, the assay may be carried out with cells that express aSyk kinase. The cells may express the Syk kinase endogenously or theymay be engineered to express a recombinant Syk kinase. The cells mayoptionally also express the Syk kinase substrate. Cells suitable forperforming such confirmation assays, as well as methods of engineeringsuitable cells will be apparent to those of skill in the art. Specificexamples of biochemical and cellular assays suitable for confirming theactivity of the 2,4-pyrimidinediamine compounds are provided in theExamples section.

Generally, compounds that are Syk kinase inhibitors will exhibit an IC₅₀with respect to a Syk kinase activity, such as the ability of Syk kinaseto phosphorylate a synthetic or endogenous substrate, in an in vitro orcellular assay in the range of about 20 μM or less. Skilled artisanswill appreciate that compounds that exhibit lower IC50s, such as in therange of 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower, areparticularly useful.

6.5 Uses and Compositions

As previously discussed, the active compounds of the invention inhibitFc receptor signaling cascades, especially those Fc receptors includinga gamma homodimer, such as the FcεRI and/or FcγRI signaling cascades,that lead to, among other things, the release and/or synthesis ofchemical mediators from cells, either via degranulation or otherprocesses. As also discussed, the active compounds are also potentinhibitors of Syk kinase. As a consequence of these activities, theactive compounds of the invention may be used in a variety of in vitro,in vivo and ex vivo contexts to regulate or inhibit Syk kinase,signaling cascades in which Syk kinase plays a role, Fc receptorsignaling cascades, and the biological responses effected by suchsignaling cascades. For example, in one embodiment, the compounds may beused to inhibit Syk kinase, either in vitro or in vivo, in virtually anycell type expressing Syk kinase. They may also be used to regulatesignal transduction cascades in which Syk kinase plays a role. SuchSyk-dependent signal transduction cascades include, but are not limitedto, the FcεRI, FcγRI, FcγRIII, BCR and integrin signal transductioncascades. The compounds may also be used in vitro or in vivo toregulate, and in particular inhibit, cellular or biological responseseffected by such Syk-dependent signal transduction cascades. Suchcellular or biological responses include, but are not limited to,respiratory burst, cellular adhesion, cellular degranulation, cellspreading, cell migration, cell aggregation, phagcytosis, cytokinesynthesis and release, cell maturation and Ca²⁺ flux. Importantly, thecompounds may be used to inhibit Syk kinase in vivo as a therapeuticapproach towards the treatment or prevention of diseases mediated,either wholly or in part, by a Syk kinase activity. Non-limitingexamples of Syk kinase mediated diseases that may be treated orprevented with the compounds are those discussed in more detail, below.

In another embodiment, the active compounds may be used to regulate orinhibit the Fc receptor signaling cascades and/or FcεRI- and/orFcγRI-mediated degranulation as a therapeutic approach towards thetreatment or prevention of diseases characterized by, caused by and/orassociated with the release or synthesis of chemical mediators of suchFc receptor signaling cascades or degranulation. Such treatments may beadministered to animals in veterinary contexts or to humans. Diseasesthat are characterized by, caused by or associated with such mediatorrelease, synthesis or degranulation, and that can therefore be treatedor prevented with the active compounds include, by way of example andnot limitation, atopy or anaphylactic hypersensitivity or allergicreactions, allergies (e.g., allergic conjunctivitis, allergic rhinitis,atopic asthma, atopic dermatitis and food allergies), low grade scarring(e.g., of scleroderma, increased fibrosis, keloids, post-surgical scars,pulmonary fibrosis, vascular spasms, migraine, reperfusion injury andpost myocardial infarction), diseases associated with tissue destruction(e.g., of COPD, cardiobronchitis and post myocardial infarction),diseases associated with tissue inflammation (e.g., irritable bowelsyndrome, spastic colon and inflammatory bowel disease), inflammationand scarring.

When used to treat or prevent such diseases, the active compounds may beadministered singly, as mixtures of one or more active compounds or inmixture or combination with other agents useful for treating suchdiseases and/or the symptoms associated with such diseases. The activecompounds may also be administered in mixture or in combination withagents useful to treat other disorders or maladies, such as steroids,membrane stablizers, 5LO inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, COX inhibitors, methotrexate, anti-TNF drugs, retuxin, PD4inhibitors, p38 inhibitors, PDE4 inhibitors, and antihistamines, to namea few. The active compounds may be administered per se in the form ofprodrugs or as pharmaceutical compositions, comprising an activecompound or prodrug.

Pharmaceutical compositions comprising the active compounds of theinvention (or prodrugs thereof) may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making levigating,emulsifying, encapsulating, entrapping or lyophilization processes. Thecompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients or auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically.

The active compound or prodrug may be formulated in the pharmaceuticalcompositions per se, or in the form of a hydrate, solvate, N-oxide orpharmaceutically acceptable salt, as previously described. Typically,such salts are more soluble in aqueous solutions than the correspondingfree acids and bases, but salts having lower solubility than thecorresponding free acids and bases may also be formed.

Pharmaceutical compositions of the invention may take a form suitablefor virtually any mode of administration, including, for example,topical, ocular, oral, buccal, systemic, nasal, injection, transdermal,rectal, vaginal, etc., or a form suitable for administration byinhalation or insufflation.

For topical administration, the active compound(s) or prodrug(s) may beformulated as solutions, gels, ointments, creams, suspensions, etc. asare well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) may be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets may be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Compoundswhich are particularly suitable for oral administration includeCompounds R940350, R935372, R935193, R927050 and R935391.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)may be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit maybe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

A specific example of an aqueous suspension formulation suitable fornasal administration using commercially-available nasal spray devicesincludes the following ingredients: active compound or prodrug (0.5-20mg/ml); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN®80; 0.5-5 mg/ml); carboxymethylcellulose sodium or microcrystallinecellulose (1-15 mg/ml); phenylethanol (1-4 mg/ml); and dextrose (20-50mg/ml). The pH of the final suspension can be adjusted to range fromabout pH5 to pH7, with a pH of about pH 5.5 being typical.

Another specific example of an aqueous suspension suitable foradministration of the compounds via inhalation, and in particular forsuch administration of Compound R921218, contains 1-20 mg/mL Compound orprodrug, 0.1-1% (v/v) Polysorbate 80 (TWEEN®80), 50 mM citrate and/or0.9% sodium chloride.

For ocular administration, the active compound(s) or prodrug(s) may beformulated as a solution, emulsion, suspension, etc. suitable foradministration to the eye. A variety of vehicles suitable foradministering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the active compound(s) or prodrug(s) can beformulated as a depot preparation for administration by implantation orintramuscular injection. The active ingredient may be formulated withsuitable polymeric or hydrophobic materials (e.g., as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptionmay be used. To this end, permeation enhancers may be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems may be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat may be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration.

6.6 Effective Dosages

The active compound(s) or prodrug(s) of the invention, or compositionsthereof, will generally be used in an amount effective to achieve theintended result, for example in an amount effective to treat or preventthe particular disease being treated. The compound(s) may beadministered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmaticattack, or a reduction in the frequency or severity of asthmaticepisodes. Therapeutic benefit also includes halting or slowing theprogression of the disease, regardless of whether improvement isrealized.

For prophylactic administration, the compound may be administered to apatient at risk of developing one of the previously described diseases.For example, if it is unknown whether a patient is allergic to aparticular drug, the compound may be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration may be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound may be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundmay be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound may be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages may be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals may be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay, such as the in vitro CHMC or BMMC and other in vitroassays described in the Examples section. Calculating dosages to achievesuch circulating blood or serum concentrations taking into account thebioavailability of the particular compound is well within thecapabilities of skilled artisans. For guidance, the reader is referredto Fingl & Woodbury, “General Principles,” In: Goodman and Gilman's ThePharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latestedition, Pagamonon Press, and the references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, 1995, Allergy 50(21 Suppl):6-9,discussion 34-38 and Tumas et al., 2001, J. Allergy Clin. Immunol.107(6):1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., 2000, Arzneimittelforschung50(11):1037-42; Kawaguchi et al., 1994, Clin. Exp. Allergy 24(3):238-244and Sugimoto et al., 2000, Immunopharmacology 48(1):1-7. Suitable animalmodels of allergic conjunctivitis are described in Carreras et al.,1993, Br. J. Ophthalmol. 77(8):509-514; Saiga et al., 1992, OphthalmicRes. 24(1):45-50; and Kunert et al., 2001, Invest. Ophthalmol. Vis. Sci.42(11):2483-2489. Suitable animal models of systemic mastocytosis aredescribed in O'Keefe et al., 1987, J. Vet. Intern. Med. 1(2):75-80 andBean-Knudsen et al., 1989, Vet. Pathol. 26(1):90-92. Suitable animalmodels of hyper IgE syndrome are described in Claman et al., 1990, Clin.Immunol. Immunopathol. 56(1):46-53. Suitable animal models of B-celllymphoma are described in Hough et al., 1998, Proc. Natl. Acad. Sci. USA95:13853-13858 and Hakim et al., 1996, J. Immunol. 157(12):5503-5511.Suitable animal models of atopic disorders such as atopic dermatitis,atopic eczema and atopic asthma are described in Chan et al., 2001, J.Invest. Dermatol. 117(4):977-983 and Suto et al., 1999, Int. Arch.Allergy Immunol. 120(Suppl 1):70-75. Ordinarily skilled artisans canroutinely adapt such information to determine dosages suitable for humanadministration. Additional suitable animal models are described in theExamples section.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval may be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds may be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) may be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The invention having been described, the following examples are offeredby way of illustration and not limitation.

7. EXAMPLES 7.1 Synthesis of Starting Materials and Intermediates Usefulfor Synthesizing The 2,4-Pyrimidinediamine Compounds According toSchemes (I)-(V)

Sections 7.1.1-7.1.141 of copending application Ser. No. 10/355,543filed Jan. 31, 2003 describe the synthesis of various2-chloro-4N-substituted-pyrimidinediamine useful for synthesizing2,4-pyrimidinediamine compounds described herein. The content of theseSections 7.1.1-7.1.141 are incorporated by reference.

7.2 Synthesis of Amines and Amine Precursors

Sections 7.2.1-7.2.47 of copending application Ser. No. 10/355,543 filedJan. 31, 2003 describe the synthesis of various amines useful forsynthesizing 2,4-pyrimidinediamine compounds described herein. Thecontent of these Sections 7.2.1-7.2.47 are incorporated herein byreference.

7.3 Synthesis of 2,4-Pyrimidinediamines

Sections 7.3.1-7.3.1165 of copending application Ser. No. 10/355,543filed Jan. 31, 2003 describe the synthesis of the 2,4-pyrimidinediaminecompounds listed below. The content of these Sections 7.3.1-7.3.1165 areincorporated herein by reference. Compounds R008951, R008952, R008953,R008955, R008956, R008958, R070153 and R070790 as described in Example7.3.1099 below (Section 7.3.1099 of copending Ser. No. 10/355,543 filedJan. 31, 2003) were purchased from Contact Services.

Example Compound Chemical Name 7.3.1 R926069N2,N4-Bis(4-ethoxyphenyl)-2,4-pyrimidinediamine 7.3.2 R921218N2,N4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.3 R926017N2,N4-Bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.4 R926018N2,N4-Bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.5 R926037N2,N4-Bis(3,4-tetrafluoroethylendioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.6 R926038N2,N4-Bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.7R926039N2,N4-Bis(4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.8 R926064 N2,N4-Bis(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.9 R926339N2,N4-Bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.10 R926340N2,N4-Bis(4-ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.11 R926341N2,N4-Bis(-3-hydroxy-4-methylphenyl)-5-fluoro-2,4-pyrimidinediaminediamine7.3.12 R926342N2,N4-Bis[4-(2-methoxyethyleneoxy)phenyl]-5-fluoro--2,4-pyrimidinediamine7.3.13 R909237N2,N4-Bis(dihydrobenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediaminediamine7.3.14 R926065 N2,N4-Bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.15 R926086N2,N4-Bis[4-(N,N-dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.16 R926109N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.17R926110 N2,N4-Bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.18 R926114N2,N4-Bis[4-(N-morpholino)phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.19R926206 N2,N4-Bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.20R926209 N2,N4-Bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.21R926222 N2,N4-Bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.22 R926223N2,N4-Bis(3-chloro-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.23R926224 N2,N4-Bis(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.24R926225 N2,N4-Bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.25R926240N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.26 R926254(±)-N2,N4-Bis[4-methoxycarbonyl(α-methyl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.27 R926255N2,N4-Bis[(3-methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.28 R926387N2,N4-Bis(3-acetyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.29R926394 N2,N4-Bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.30 R926398 N2,N4-Bis(2-phenylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.31 R926404 N2,N4-Bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine7.3.32 R926399N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.33 R926400N2,N4-Bis[(2-methoxy-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.34 R926401N2,N4-Bis[(2-methoxy-5-methyl-4-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.35 R926402N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.36 R926403N2,N4-Bis[(3-phenyl)phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.37R926405 N2,N4-Bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.38R926469N2,N4′-Bis(4-hydroxy-3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.39 R926574N2,N4-Bis[4-(tert-butoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.40 R926582 N2,N4-Bis(indol-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.41 R926319N2,N4-Bis(4-cyanomethylphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.42 R926320N2,N4-Bis(3-indazol-6-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine 7.3.43R926321 N2,N4-Bis(3-indazol-7-yl)-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.44 R926325N2,N4-Bis[6-(1,4-benzoxazine-3-onyl)]-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.45 R926331N2,N4-Bis(4-ethoxycarbonylmethyleneaminophenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.46 R926058N2,N4-Bis(4-ethoxyphenyl)-6-methoxycarbonyl-2,4-pyrimidinediamine 7.3.47R926068 N2,N4-Bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidinediamine 7.3.48R926072 N2,N4-Bis(4-ethoxyphenyl)-6-chloro-2,4-pyrimidinediamine 7.3.49R926242N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine 7.3.50R926243 N2,N4-Bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.51R926248 N2,N4-Bis(3-hydroxyphenyl)-5-methyl-2,4-pyrimidinediamine 7.3.52R926249 N2,N4-Bis(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.53 R926256N2,N4-Bis[(4-methoxycarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine7.3.54 R926257(±)-N2,N4-Bis[4-methoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-2,4-pyrimidinediamine7.3.55 R926258N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-pyrimidinediamine7.3.56 R926259(±)-N2,N4-Bis[4-ethoxycarbonyl(alpha-methyl)methyleneoxyphenyl]-5-methyl-2,4-pyrimidinediamine 7.3.57 R926397N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-methyl-2,4-pyrimidinediamine7.3.58 R940089N2,N4-Bis-(3,4-dimethoxypenyl)-5-nitro-2,4-pyrimidinediamine 7.3.59R940090 N2,N4-Bis-(4-ethoxypenyl)-5-nitro-2,4-pyrimidinediamine 7.3.60R940095N2,N4-Bis-(3,4-ethylenedioxyphenyl)-5-nitro-2,4-pyrimidinediamine 7.3.61R940096N2,N4-Bis-[(4-ethoxycarbonylmethyleneoxy)phenyl]-5-nitro-2,4-pyrimidinediamine7.3.62 R940100N2,N4-Bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine7.3.63 R940215N2,N4-Bis-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.64 R940216N2,N4-Bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.65 R940217N2,N4-Bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.66 R940222N2,N4-Bis-(4-Acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.67R940297 N2,N4-Bis(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.68 R926688N2,N4-Bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.69R925800 N2,N4-Bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine7.3.70 R925801N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4-pyrimidinediamine7.3.71 R926594 N2,N4-Bis(indol-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.72 R926604 N2,N4-Bis(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.73 R926605N2,N4-Bis[4-(methoxycarbonylmethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.74 R926616N2,N4-Bis(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.75 R926617 N2,N4-Bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.76 R926620N2,N4-Bis(4-methoxymethyl)coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine7.3.77 R925757N2,N4-Bis(3-(hydroxymethyl)phenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.78R925767N2,N4-Bis[(2R)-hydroxy-(1S)-methyl-2-phenylethyl]-5-fluoro-2,4-pyrimidinediamine7.3.79 R925768N2,N4-Bis(2-hydroxy-2-phenylethyl)-5-fluoro-2,4-pyrimidinediamine 7.3.80R925769 N2,N4-Bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine 7.3.81R925770 N2,N4-Bis(piperonyl)-5-fluoro-2,4-pyrimidineamine 7.3.82 R925772N2,N4-Dibenzyl-5-fluoro-2,4-pyrimidinediamine 7.3.83 R925776N2,N4-Bis(3,4-methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.84 R925791N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-fluoro-2,4-pyrimidinediamine7.3.85 R945057 N2,N4-Bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.86 R926234 N2,N4-Bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.87 R926675N2,N4-Bis(3-chloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.88 R926676N2,N4-Bis[3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.89 R926681N2,N4-Bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.90 R926682N2,N4-Bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.91R926683N2,N4-Bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.92 R926701N2,N4-Bis(4-isopropoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.93R925771 N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine7.3.94 R925778 N2,N4-Bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine7.3.95 R925779N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-bromo-2,4-pyrimidinediamine7.3.96 R925792N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-5-bromo-2,4-pyrimidinediamine 7.3.97R925798 N2,N4-Bis(2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine 7.3.98R925799N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine 7.3.99R925802N2,N4-Bis(4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine7.3.100 R925803 N2,N4-Bis(3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine7.3.101 R925773N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-cyano-2,4-pyrimidinediamine 7.3.102R925774 N2,N4-Bis(3-hydroxyphenyl)-5-cyano-2,4-pyrimidinediamine 7.3.103R925775N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-cyano-2,4-pyrimidinediamine7.3.104 R935192N2,N4-Bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.105 R935205N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.106 R935211N2,N4-Bis[1-(methoxycarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.107 R935188 N2,N4-Bis(indazolin-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.108 R935189 N2,N4-Bis(indazolin-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.109 R925814N2,N4-Bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-pyrimidinediamine7.3.110 R925815N2,N4-Bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine7.3.111 R925819N2,N4-Bis(methoxycarbonylbenzyl)-5-cyano-2,4-pyrimidinediamine 7.3.112R926662N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-cyano-2,4-pyrimidinediamine7.3.113 R935000N2,N4-Bis(2-methoxy-5-phenylphenyl)-5-methyl-2,4-pyrimidinediamine7.3.114 R935001N2,N4-Bis[(2-methyl-5-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine7.3.115 R935002N2,N4-Bis[(4-methoxy-3-phenyl)phenyl]-5-methyl-2,4-pyrimidinediamine7.3.116 R935003N2,N4-Bis[(4-phenyl-2-methoxy-5-methyl)phenyl]-5-methyl-2,4-pyrimidinediamine7.3.117 R935004N2,N4-Bis[[di-(4-methoxyphenyl)]methyl]-5-fluoro-2,4-pyrimidinediamine7.3.118 R935005 N2,N4-Bis(diphenylmethyl)-5-fluoro-2,4-pyrimidinediamine7.3.119 R935006N2,N4-Bis[di-(4-chlorophenyl)methyl]-5-fluoro-2,4-pyrimidinediamine7.3.120 R935016N2,N4-Bis[1(R)-4-methoxyphenylethyl]-5-bromo-2,4-pyrimidineamine 7.3.121R935075N2,N4-Bis[3-(2-hydroxyethoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.122 R935076N2,N4-Bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.123 R935077N2,N4-Bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.124 R935114N2,N4-Bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine7.3.125 R935162N2,N4-Bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.126 R935163 N2,N4-Bis(3-chloro-4-fluoropheny)-2,4-pyrimidinediamine7.3.127 R925849N2,N4-Bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine7.3.128 R925852N2,N4-Bis(3,4-ethylendioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine7.3.129 R925864N2,N4-Bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine7.3.130 R925790N2,N4-Bis[2-(4-hydroxyphenyl)ethyl]-2,4-pyrimidinediamine 7.3.131R925804 N2,N4-Bis(2-phenylphenyl)-2,4-pyrimidinediamine 7.3.132 R925805N2,N4-Bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine 7.3.133R945041N2,N4-Bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.134 R925806N2,N4-Bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine 7.3.135R925807 N2,N4-Bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine 7.3.136R925808N2,N4-Bis(2-methoxy-5-methyl-4-phenylphenyl)-2,4-pyrimidinediamine7.3.137 R925862N2,N4-Bis[4-(ethoxycarbonylmethyleneoxy)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine7.3.138 R925863N2,N4-Bis(3-hydroxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine7.3.139 R926663N2,N4-Bis[4-(ethoxycarbonylmethyl)phenyl]-5-trifluoromethyl-2,4-pyrimidinediamine7.3.140 R926623N2,N4-Bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.141 R926461N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine 7.3.142R945051 N2,N4-Bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.143R945145N2,N4-Bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine7.3.144 R945152N2,N4-Bis[4-(N-benzylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.145 R945038N2,N4-Bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.146 R950160 N2,N4-Bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.147 R950091 N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.148 R950122 N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.149 R950182N2,N4-Bis[3-(dimethylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.150 R950130 N2,N4-Bis(3-amino-4-methylphenyl)-2,4-pyrimidinediamine7.3.151 R950129N2,N4-Bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.152R950083N2,N4-Bis[(4-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.153 R950090N2,N4-Bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.154 R950092N2,N4-Bis(3-cyano-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.155 R950100N2,N4-Bis[3-methylsulfonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.156 R950108N2,N4-Bis[3-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.157 R950120N2,N4-Bis[4-(tert-butoxycarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.158 R950170N2,N4-Bis[2-[2-(methylamino)ethyleneaminocarbonyl]-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.159 R950167N2,N4-Bis[2-(2-hydroxyethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.160 R950168N2,N4-Bis[2-(2-aminoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.161 R950169N2,N4-Bis[2-(2-(N-benzylamino)ethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.162 R950172N2,N4-Bis[2-(N-morpholinocarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.163 R950173N2,N4-Bis[2-(2-N-morpholinoethyleneamoinocarbonyl)-benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.164 R950135N2,N4-Bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.165R950138N2,N4-Bis(3-amino-2,4-difluorophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.166 R950139N2,N4-Bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.167R950134N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.168 R950140N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.169 R950141N2,N4-Bis(3-amino-5-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.170R950093N2,N4-Bis(4-hydroxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.171 R950107 N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamineHydrogen Chloride salt 7.3.172 R950121N2,N4-Bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine HydrogenChloride Salt 7.3.173 R950109N2,N4-Bis(3-aminophenyl)-2,4-pyrimidinediamine 7.3.174 R950131N2,N4-Bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine 7.3.175R950142 N2,N4-Bis(3-amino-4-ethoxyphenyl)-2,4-pyrimidinediamine 7.3.176R950132 N2,N4-Bis(3-amino-5-methoxycarbonylphenyl)-2,4-pyrimidinediamine7.3.177 R950143N2,N4-Bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.178R950133 N2,N4-Bis(3-amino-5-chlorophenyl)-2,4-pyrimidinediamine 7.3.179R950125N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.180 R950123N2,N4-Bis[3-amino-4-(N-phenylamino)-phenyl]-2,4-pyrimidinediamine7.3.181 R950157N2,N4-Bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.182R950158 N2,N4-Bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.183 R950159N2,N4-Bis(3-amino-4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.184R950146 N2,N4-Bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.185 R950147N2,N4-Bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.186R950148 N2,N4-Bis(4-fluoro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.187 R950144N2,N4-Bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine(R950144) 7.3.188 R950149N2,N4-Bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.189R950150N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.190 R950151N2,N4-Bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.191 R950152 N2,N4-Bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine7.3.192 R950153 N2,N4-Bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine7.3.193 R950154 N2,N4-Bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine7.3.194 R950155 N2,N4-Bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine7.3.195 R950156N2,N4-Bis(2-hydroxyethyleneamino-5-nitrophenyl)-2,4-pyrimidinediamine7.3.196 R950166N2,N4-Bis[3-(N-isopropyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine7.3.197 R950171N2,N4-Bis[3-N-(2-hydroxy-1-methylethyl)aminophenyl]-5-fluoro-2,4-pyrimidinediamine7.3.198 R950177N2,N4-Bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.199 R950178N4-(3-Aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.200 R950179N2-(3-Aminophenyl)-N4-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.201 R950184N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.202 R950183N2,N4-Bis(3-ethoxycarbonylmethyleneaminophenyl)-N2-(ethoxycarbonylmethyl)-5-fluoro-2,4-pyrimidinediamine 7.3.203 R950180N2-(3-Aminophenyl)-N4-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamineand N4-(3-Aminophenyl)-N2-(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.204 R950181N2,N4-Bis(3-hydroxyethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.205 R950174N2,N4-Bis[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.206 R950175N2-(3-Aminophenyl)-N4-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.207 R950176N4-(3-Aminophenyl)-N2-[3-(N-benzyloxyethyleneamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.208 R926210N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.209 R925758N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine7.3.210 R925760N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(hydroxymethyl)phenyl]-2,4-pyrimidinediamine7.3.211 R925765N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxy-2-phenylethyl)-2,4-pyrimidinediamine7.3.212 R925766N2-(3,4-Ethylendioxyphenyl)-5-fluoro-N4-[(2R)-hydroxy-(1S)-methyl-2-phenylethyl)-2,4-pyrimidinediamine 7.3.213 R925794N4-Cyclohexyl-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.214 R925795N4-(4-Carboxycyclohexyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.215 R925796N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.216 R925823N2-Allyl-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.217 R926237N4-(3,4-Ethylenedioxyphenyl)-N2-(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.218 R926690N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.219 R9267045-Fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.220 R9263765-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine7.3.221 R909236N2-[4-(2-N,N-Dimethylamino)ethoxyphenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.222 R909238N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.223 R909241N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.224 R909242N4-(1,4-Benzoxazin-6-yl)-N2-[3-ethoxyocarbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.225 R909243N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamineN4-(1,4-Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.226 R909245N4-(1,4-Benzoxazin-6-yl)-N2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.227 R909246N4-(1,4-Benzoxazin-6-yl)-N2-(3-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.228 R909248N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[4-(2-hydroxyethyl)oxyphenyl]-2,4-pyrimidinediamine7.3.229 R909250N2-(2,3-Dihydrobenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.230 R909255N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.231 R9267065-Fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.232 R9266995-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.233 R926709N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.234 R9267105-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.235 R926711N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.236 R926716N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(tetrahydro-(1H)-pyrrol-1-ylsulfonyl)phenyl]-2,4-pyrimidinediamine 7.3.237 R926717N2-[3-[4-(2-Chloro-6-fluorobenzyl)piperazino]propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.238 R926719N2-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.239 R926721N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.240 R926722N4-[(5-Chloro-1-benzothiophen-3-yl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.241 R926723N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-N2-(3,4-ethylenedioxy)-5-fluoro-2,4-pyrimidinediamine7.3.242 R945168N2-(2,3-Dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.243 R926724N4-[2-[(2-Chloro-6-fluorobenzyl)thio]ethyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.244 R926743N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-phenyl-5-methylisoxazol-4-yl)-2,4-pyrimidinediamine7.3.245 R926744N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dimethylisoxazol-4-yl)-2,4-pyrimidinediamine7.3.246 R926727N2-[2-(Ethoxycarbonylmethylenethio)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.247 R926740N2-[2-(Ethoxycarbonylmethyleneoxy)pyridin-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.248 R9257975-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.249 R925822N2-Allyl-5-bromo-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.250R9258205-Cyano-N2-(3,4-ethylenedioxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine7.3.251 R935172N4-[4-[Ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.252 R935173N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine 7.3.253 R9351825-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.254 R9351855-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.255 R935187N4-[3-(1-Bis(ethoxycarbonyl)ethoxy)phenyl]-5-fluoro-N2-[4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.256 R935190N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazolin-6-yl)-2,4-pyrimidinediamine.7.3.257 R9351915-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazolin-6-yl)-2,4-pyrimidinediamine7.3.258 R935193N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.259 R9351945-Fluoro-N4-(3-hydroxyphenyl)-N2-(1-methy-indazoline-5-yl)-2,4-pyrimidinediamine7.3.260 R9351975-Fluoro-N2-(indazoline-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.261 R935198N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.262 R9351995-Fluoro-N4-(3-hydroxyphenyl)-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.263 R9352035-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.264 R9352045-Fluoro-N2-(3-hydroxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.265 R935207N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.266 R935208N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.267 R9352095-Fluoro-N2-[4-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine 7.3.268 R9352145-Fluoro-N2-(3,5-dimethoxyphenyl)-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.269 R9352155-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.270 R9352185-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.271 R935219N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.272 R9352205-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.273 R950203N4-(3,4-Ethylenedioxyphenyl)-N2-(3-furanylmethylene)-5-fluoro-2,4-pyrimidinediamine7.3.274 R950204N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(4-methoxyphenyloxy)ethyl]-2,4-pyrimidinediamine7.3.275 R950205N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.276 R950206N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.277 R950201N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(methylthio)-1,3-benzothiaz-6-yl]-2,4-pyrimidinediamine 7.3.278 R950213N2-[2,3-Dihydrobenzo[b]furan-5-ylmethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.279 R950214N2-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.280 R9502125-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methylthio)-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine7.3.281 R950227N2-(3-Aminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.282 R950253N2-(1,4-Benzoxazin-6-yl)]-5-fluoro-N4-(3-nitrophenyl)-2,4-pyrimidinediamine7.3.283 R950215N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.284 R950229N2-(Ethoxycarbonylmethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine 7.3.285 R9258215-Cyano-N2-(3-hydroxyphenyl)-N4-(methoxycarbonylbenzyl)-2,4-pyrimidinediamine7.3.286 R9266805-Fluoro-N4-[2-fluoro-4-(methoxymethyleneoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.287 R926748N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine7.3.288 R9267495-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine7.3.289 R926750N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine7.3.290 R9267515-Fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine7.3.291 R945063N4-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.292 R945071N4-[4-(Cyanomethyleneoxy)phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.293 R945109N4-(3-Cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.294 R945110N4-(3-Cyanophenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine7.3.295 R9451175-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(indol-3-yl)ethyl]-2,4-pyrimidinediamine7.3.296 R9451185-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.297 R945124N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.298 R9451255-Fluoro-N4-(4-isopropoxyphenyl)-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.299 R945064N2-[4-(Aminocarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.300 R9451325-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.301 R945133N2-[4-(Aminocarbonylmethoxy)phenyl]-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.302 R945128N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.303 R9451295-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.304 R945137N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.305 R9451385-Fluoro-N2-(4-isopropoxyphenyl)-N4-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.306 R945139N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.307 R945146N4-(Benzothiophen-3-ylmethyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.308 R9451475-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-pyridylmethyl)-2,4-pyrimidinediamine7.3.309 R945148N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.310 R945151N4-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.311 R945153N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.312 R945155N4-[4-(N-Benzylpiperazino)phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.313 R945162N2-[(2,5-Dimethyl-3-furyl)methyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.314 R945163N2-[4-(N-Benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.315 R945164N2-(Benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.316 R9451655-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-pyridylmethyl)-2,4-pyrimidinediamine7.3.317 R9451665-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-pyridylmethyl)-2,4-pyrimidinediamine7.3.318 R926802N4-(3,5-Dimethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.319 R926803N4-(3,5-Dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine7.3.320 R926108N2-(3,4-Dimethoxyphenyl)-N4-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.321 R926146N4-(4-Ethoxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.322 R926213N4-(4-Ethoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.323 R926145N4-(3,4-Dimethoxyphenyl)-N2-(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.324 R926147N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.325 R926113N2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.326 R926395N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.327 R9263965-Bromo-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.328 R926211N2-(4-Ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.329 R926212N2-(3,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.330 R926218N2-(3-Chloro-4-fluorophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.331 R926219N2-(4-tert-Butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.332 R926220N4-(3,4-Ethylenedioxyphenyl)-N2-(4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.333 R926221N4-(3,4-Ethylenedioxyphenyl)-N2-(3-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine7.3.334 R926229N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-methoxyethyl)-2,4-pyrimidinediamine7.3.335 R926230N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxybenzyl)-2,4-pyrimidinediamine7.3.336 R926386N2-(2,2-Difluorobenzodioxol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.337 R926476N2-(2-Ethoxycarbonylindol-5-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.338 R926480N2-(4-Cyanomethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.339 R926482N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.340 R925745N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.341 R925746N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-hydroxyethyl)-2,4-pyrimidinediamine7.3.342 R925747N2-(4-Ethoxycarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.343 R940233N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.344 R940235N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.345 R940250N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamineN2-(3,4-Dimethoxyphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine 7.3.346 R940251N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine 7.3.347 R940253N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[4-[3-(N-morpholinyl)propyl]oxyphenyl]-2,4-pyrimidinediamine 7.3.348 R940266N2-(3-tert-Butylphenyl)-N4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine7.3.349 R940284 Mixture of5-Fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine and5-fluoro-N2-(2-ethoxoxycarbonylbenzofur-5-yl)-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine 7.3.350 R940281N4-(3-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine7.3.351 R9402835-fluoro-N4-(3-isopropylphenyl)-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine7.3.352 R926786N2-(1,1-Dihydroisobenzofuran-1-one-6-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.353 R926787N2-[3-(3-Acetamidophenoxy)propyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.354 R926788N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.355 R926789N2-(2,4-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.356 R926790N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine7.3.357 R926791N2-(3,5-Dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.358 R926792N2-(2,5-Dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.359 R926793N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine7.3.360 R926795N4-(3,5-Dimethoxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.361 R926797N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine 7.3.362 R926798N4-(3-Hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine 7.3.363 R9266145-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine7.3.364 R926615N2-(2-Ethoxycarbonylindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.365 R926777N2-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.366 R9267785-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-isopropylphenyl)-2,4-pyrimidinediamine7.3.367 R926779 5-FluoroN4-(3-hydroxyphenyl)-N2-(5-methyl-4-oxazolyl-2-phenyl)-2,4-pyrimidinediamine7.3.368 R926780N2-(3.5-Dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine(R926780) 7.3.369 R926572N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine 7.3.370 R9264875-Fluoro-N4-(3-isopropoxyphenyl)-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine7.3.371 R926474N4-(4-tert-Butylphenyl)-N2-(2-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.372 R926477N4-(4-tert-Butylphenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine7.3.373 R926485N2-(3,4-Ethylenedioxyphenyl)-N4-(2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.374 R926774N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.375 R926775N4-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.376 R945177N4-(4-Aminocarbonylmethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.377 R9350195-Fluoro-N2-(3-hydroxyphenyl)-N4-[di-(4-chlorophenyl)methyl]-2,4-pyrimidinediamine7.3.378 R935020N4-(Fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.379 R935021(±)-5-Fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.380 R935023(±)-5-Bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.381 R9350255-Bromo-N2-(3-hydroxyphenyl)-N4-(N-methyl-2-carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine7.3.382 R935029 4-Amino-5-bromo-N2-(3-hydroxyphenyl)-2-pyrimidineamine7.3.383 R9351345-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.384 R9351355-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.385 R935136N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.386 R9351375-Fluoro-N4-(2-methoxycarbonylbenzofura-5-yl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.387 R9351385-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.388 R9351395-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.389 R935140N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.390 R9351415-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.391 R9351425-Fluoro-N4-(4-isopropoxyphenyl)-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.392 R935143N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.393 R9351445-Fluoro-N2-(4-isopropoxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.394 R935145N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.395 R9351465-Fluoro-N2-(2-methoxycarbonylbenzofura-5-yl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.396 R9351475-Fluoro-N2-(3-hydroxyphenyl)-N4-[4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.397 R935148N2-(3,4-Ethylenedioxyphenyl)-N4-[4-[(1-ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.398 R935150N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.399 R935179N2-[4-(2,3-Dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxypheny)-5-fluoro-2,4-pyrimidinediamine 7.3.400 R935180N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.401 R935175N2-[4-(2,3-Dihydroxypropoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.402 R935169N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.403 R9351645-Fluoro-N4-(4-isopropoxyphenyl)-N2-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamine 7.3.404 R9351655-Fluoro-N2-(4-isopropoxyphenyl)-N4-[(N-methyl-2-carbomethoxy)pyrrole-4-yl]-2,4-pyrimidinediamine 7.3.405 R935166N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[(N-methyl-2-methoxycarbonyl)pyrrol-4-yl]-2,4-pyrimidinediamine 7.3.406 R935167N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.407 R9351595-Fluoro-N4-(4-isopropoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.408 R935157N4-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.409 R935152N2-[4-[(1-Ethoxycarbonyl-1-methyl)ethyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.410 R940257N2-(3-tert-Butylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.411 R940258 Mixture ofN4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine andN4-(3-chloro-4-hydroxy-5-methylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.412 R940260N2-(3-tert-Butylphenyl)-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R940260) 7.3.413 R940261N2-[2-(N-Benzylpiperazino)ethyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.414 R940262N2-[2-(N-Benzylpiperazino)ethyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.415 R940263N2-[4-(N-Benzylpiperidino)]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.416 R940264N2-[4-(N-Benzylpiperidino)]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.417 R940270N4-(3-tert-Butylphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.418 R940271N4-(3-tert-Butylphenyl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.419 R940275N2-(3-tert-Butylcarbonylaminophenyl)-N4-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.420 R940294N4-(3,3-Dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.421 R940285N2-[3-Ethoxycarbonylmethyleneoxyphenyl]-N4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.422 R926804N2-(3,5-Dimethoxyphenyl)-N4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.423 R926805N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-trifluoromethylphenyl)]-2,4-pyrimidinediamine7.3.424 R926808N2-(2-Ethoxycarbonylindol-7-yl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine7.3.425 R926809N4-[4-(4,5-Dichloro-1H-imidazol-1-yl)phenyl]-5-fluoro-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.426 R926813N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine7.3.427 R926814N2-(2-Ethoxycarbonylindol-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyridinediamine7.3.428 R950207N2-(3-Aminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.429 R950186N4-(3,4-Ethylenedioxyphenyl)-N2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.430 R950185N4-(3,5-Dichloro-4-hydroxyphenyl)-N2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.431 R950162N4-(3-Aminophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofurane-5-yl)-2,4-pyrimidinediamine7.3.432 R950163N4-(3-Aminophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.433 R950164N4-(3-Aminophenyl)-5-fluoro-N2-(3-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.434 R950165N4-(3-Aminophenyl)-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.435 R950210N2-(3-Furylmethylene)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.436 R9502115-Fluoro-N4-(3-hydroxyphenyl)-N2-(4-methoxyphenyloxyethyleneamino)-2,4-pyrimidinediamine7.3.437 R950137N4-(3-Aminophenyl)-N2-[[N3-[N4-(3-aminophenyl)]-5-fluoro-2,4-pyrimidinediamine]aminophenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.438 R950208N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(hydroxyethyleneamino)phenyl]-2,4-pyrimidinediamine 7.3.439 R950209N2-[3-Bis(hydroxyethyl)aminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.440 R9258586-Ethoxycarbonyl-N4-(ethoxycarbonylmethyl)-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-pyrimidinediamine 7.3.441 R925837N4-Benzyloxy-5-ethoxycarbonyl-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine7.3.442 R925824N4-Benzyloxy-5-ethoxycarbonyl-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.443 R945025N2,N4-Bis[4-(aminocarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.444 R945032N2,N4-Bis[4-(cyanomethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.445 R945033N2,N4-Bis[4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.446 R945034N2,N4-Bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.447 R945035N2,N4-Bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.448 R945036N2,N4-Bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.449R945037 N2,N4-Bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.450 R926412N2,N4-Bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.451 R945040N2,N4-Bis[4-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.452 R945045N2,N4-Bis[3-(ethylaminocarbonylamino)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.453 R945043N2,N4-Bis(4-hydroxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.454 R945046N2,N4-Bis[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.454 R9450475-Fluoro-N2,N4-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl],[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.454 R945048N2,N4-Bis[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.455 R945052N4-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.456 R945053N4-(4-Cyanomethyleneoxyphenyl])5-fluoro-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.457 R945056N2,N4-Bis[3-hydroxy-4-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.458 R945060N2-(4-Aminocarbonylmethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.459 R945061N2,N4-Bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.460 R945062N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.461 R945065N2,N4-Bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.462 R945066N2,N4-Bis(4-methoxy-3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.463 R945067N2,N4-Bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.464 R945068N2,N4-Bis(4-carboxy-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.465 R945070N2-(4-Cyanomethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.466 R945172N4-(4-Cyanomethyleneoxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.467 R945096N2,N4-Bis[4-[2-methoxyimino(amino)ethyleneoxy]phenyl]-5-fluoro-2,4-pyrimidinediamine7.3.468 R945097N2-(4-Carboxymethyleneoxyphenyl)-N4-(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.469 R9451275-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.470 R9451305-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.471 R9451315-Fluoro-N4-(2-methoxycarbonylbenzofuran-5-yl)-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.472 R945134N4-(2-Carboxybenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.473 R945135N4-(2-Aminocarbonylbenzofuran-5-yl)-5-fluoro-N2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.474 R9451675-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(2-methoxyimino(amino)ethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.475 R945175N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[4-methoxyimino(amino)ethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.476 R926495N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.477 R921219N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.478 R909239N4-(3,4-Ethylendioxyphenyl)-5-fluoro-N2-[4-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine7.3.479 R909240N4-(3,4-Ethylendioxyphenyl)-5-fluoro-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.480 R909251N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-2-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.481 R909252N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-3-hydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.482 R909254N4-(1,4-Benzoxazin-6-yl)-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.483 R9267035-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(N-pyrrolidino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.484 R926708N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.485 R926494N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.486 R926712N4-(4-tert-Butylphenyl)-5-fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.487 R940295N4-(3-tert-Buthylpheny)-5-fluoro-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.488 R926562N2,N4-Bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.489 R926563N2,N4-Bis(4-N-pyrrolidinocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.490 R940296N4-(3-tert-Butylpheny)-N2-[3-(N-1,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.491 R940290N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine7.3.492 R9402885-Fluoro-N4-(3-isopropylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.493 R9267185-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-dimethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.494 R945149N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.495R926713N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.496 R926796N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.497 R9268005-Ethoxycarbonyl-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.498R926801N4-(3,5-Dimethoxyphenyl)-5-ethoxycarbonyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.499 R926714N4-(4-tert-Butylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.500 R926742N4-(3-Hydroxyphenyl)-5-trifluoromethyl-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.501 R9267455-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.502 R945156N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.503 R940291N4-(3-tert-Butylphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofur-5-yl]-2,4-pyrimidinediamine 7.3.504 R926505N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.505 R9267465-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.506 R9267155-Fluoro-N2-[2-(2-hydroxy-1,1-dimethylethylamino)carbonylbenzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.507 R9267305-Fluoro-N4-(4-isopropoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.508 R9451705-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.509 R9264895-Fluoro-N4-(3-isopropoxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.510 R9267725-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.511 R9265065-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.512 R9265085-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.513 R9267325-Fluoro-N4-[3,4-(1,1,2,2-tetrafluoroethylendioxy)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.514R940254N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.515 R940276N4-(3-tert-Butylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.516 R940277N4-(3-tert-Butylphenyl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.517 R940293N4-(3,3-Dihydroisobenzofuran-1-one-6-yl)-N2-[3-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.518 R926733N4-(3,4-Dimethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.519 R926734 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.520 R9267385-Fluoro-N4-(3-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.521 R926739 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-fluoro-N4-(3-methoxyphenyl)-2,4-pyrimidinediamine7.3.522 R945140N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.523 R9264885-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.524 R9264935-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.525 R9264975-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.526 R9265005-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.527 R9258445-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.528 R9258455-Cyano-N4-[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.529 R9258465-Cyano-N4-(3-hydroxyphenyl)-N2-[4-(N-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.530 No Rigel5-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethylphenyl)-2,4-Number pyrimidinediamine 7.3.531 R926812N4-[4-(4,5-Dichloro-1H-imidazol-1-ylphenyl)]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.532R926815N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylaminocarbonyllindol-7-yl)-2,4-pyridinediamine 7.3.533 R926484N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.534 R926492N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.535 R926496N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.536 R926498N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-2-hydroxyethylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.537 R926503N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.538 R926764N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxy-1,1-dimethylethylamino)carboxymethyleneoxyphenyl]-2,4-pyrimidinediamine7.3.539 R926765N2-[3-(N-Cyclohexylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.540 R926766N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-methyl-N-(2-hydroxyethyl)amino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine7.3.541 R926767N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.542 R925755N4-(3,4-Ethylenedioxyphenyl)-N2-[3-(N,N-dimethylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.543 R926781N2-[3-[N,N-Bis-(2-hydroxyethylamino)]carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.544 R926782 N2-[3-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.545 R926783N2-[2-(N-2,3-Dihydroxypropylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.546 R926784N2-[3-(N-1,3-Dihydroxy-2-propylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.547 R926785N2-[2-(N-1,3-Dihydroxy-2-propylamino)carbonylbenzofuran-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.548 R940265N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.549R950187N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.550 R950188N4-(3,5-Dichloro-4-hydroxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.551 R926776N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyeleneoxyphenyl]-2,4-pyrimidinediamine 7.3.552 R945173N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.553 R909253N2-[4-(2-N,N-Dimethylaminoethyl)oxyphenyl]-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.554R909247N2-(1,4-Benzoxazin-6-yl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.555 R909249N2-(4-Dihydrobenzofuranyl)-5-fluoro-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.556 R940267N2-(3-tert-Butylphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.557 R926491N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.558 R926491N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.559 R926810N2-(3,5-Dimethoxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.560 R9258515-Bromo-N2-(3,4-ethylenedioxyphenyl)-N4-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.561 R926741N2-(3-Hydroxyphenyl)-5-trifluoromethyl-N4-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.562 R925860N2,N4-Bis[4-(N-n-butylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine7.3.563 R925861N2,N4-Bis[4-(N-isopropylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine7.3.564 R925853N2,N4-Bis[4-(N-n-propylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine7.3.565 R925854N2,N4-Bis[4-(N-morphonlino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine7.3.566 R925855N2,N4-Bis[4-(N-piperidino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine7.3.567 R925859N2,N4-Bis[4-(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-cyano-2,4-pyrimidinediamine 7.3.568 R950254N4-(3-Aminophenyl)-N2-(1,4-benzoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.569 R950200 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.570 R950191N4-(3,4-Ethylenedioxyphenyl)-N2-[3-N-methylamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.571 R950192N2-[3-(N-Amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.572 R950193N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.573 R950194N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.574R950195 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-2-hydroxyethyleneamino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine7.3.575 R950196 N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)ethyleneaminocarbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.576 R950197N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.577 R950198N2-[3-(N-Benzylamino)ethyleneaminocarbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.578 R950199N2-[3-(N,N′-Bis(2-N-hydroxyethyl)amino)carbonylmethyleneaminophenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.579 R9502175-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.580 R950219N2-(3-Aminocarbonylmethyleneaminophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.581 R950220N2-[3-(N,N-Dimethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.582 R9502215-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.583 R9502225-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.584 R9502235-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[N-(N-methyl)piperazino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.585 R9502245-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-2-hydroxyethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.586 R9502255-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.587 R950226 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-2-morpholinoethylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.588 R9351845-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.589 R935196N2-[3-(1-Bis(N-methylaminocarbonyl)ethoxy)phenyl]-5-fluoro-N4-(4-isopropoxyphenyl)-2,4-pyrimidineamine 7.3.590 R9352025-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.591 R935206N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.592 R935212N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.593 R935213N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-(N-methylamino)carbonyl-fur-4-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.594 R9352165-Fluoro-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine 7.3.595 R935217N2,N4-Bis[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.596 R926486N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.597 R926490N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-morpholinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.598 R926510N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-(N-methylamino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.599 R9267705-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.600 R940255N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.601 R945142N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamine bis Hydrogen Chloride Salt 7.3.602 R945144N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine7.3.603 R945150N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamine Dihydrochloride Salt 7.3.604 R945157N4-(3,5-Dimethyl-4-methoxyphenyl)-5-fluoro-N2-[3-[2-(N-piperazino)ethoxy]phenyl]-2,4-pyrimidinediamine Dihydrochloride Salt 7.3.605 R926501N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.606 R926504N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.607 R926509N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-N-methylaminoethyl)phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.608 R926511N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[2-N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.609 R926768N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(N-homopiperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.610 R9265025-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.611 R9267695-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(N-piperazinomethylene)benzofuran-5-yl]-2,4-pyrimidinediamine Dihydrochloride Salt 7.3.612 R9267735-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-piperazino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.613 R926771N2-[3-[2-(N,N-Dimethylamino)ethyloxy]phenyl]-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.614 R940256N4-(3,5-Dimethyl-4-hydroxyphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.615 R940269N4-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-[3-[2-(N-morpholino)ethyloxy]phenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.616 R926816N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.617 R926696N4-(3,4-Ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine7.3.618 R9267005-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(hydroxymethyl)-(1H)-indol-5-yl]-2,4-pyrimidinediamine7.3.619 R9267055-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine7.3.620 R9267075-Fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.621 R926728N4-(4-tert-Butyl)phenyl)-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine7.3.622 R9267355-(Hydroxymethyl)-N2-[3-(2-hydroxyethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.623 R940287N4-(3-tert-Butylphenyl)-5-fluoro-N2-[(2-hydroxymethylene)benzofur-5-yl]-2,4-pyrimidinediamine7.3.624 R9402875-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamine7.3.625 R9402865-Fluoro-N4-(3-isopropylphenyl)-N2-[(2-hydroxymethylene]benzofur-5-yl]-2,4-pyrimidinediamine7.3.626 R940282N4-(3-tert-Butylphenyl)-5-fluoro-N2-[3-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine7.3.627 R940292N4-[3,4-Bis(hydroxymethyl)phenyl]-5-fluoro-N2-[3-(2-hydroxyethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.628 R935149N2-(3,4-Ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.629 R9351515-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.630 R9351535-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.631 R935154N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine7.3.632 R9351555-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.633 R9351565-Fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.634 R9351585-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[4-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine 7.3.635 R9351605-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.636 R9351615-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine 7.3.637 R9351685-Fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.638 R9351705-Fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.639 R9351715-Fluoro-N2-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-N4-(3-hydroxyphenyl)--2,4-pyrimidinediamine 7.3.640 R9351745-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.641 R935176N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine7.3.642 R9351775-Fluoro-N2-[4-(2-hydroxy-1,1,dimethylethyl)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.643 R9351785-Fluoro-N2-[3-(2-hydroxyethyloxy)phenyl]-N4-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.644 R935181N4-(3,5-Dimethoxyphenyl)-5-fluoro-N2-[3-(2-hydroxyethoxy)phenyl]-2,4-pyrimidinediamine7.3.645 R9351835-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine7.3.646 R9351865-Fluoro-N2-[4-(2-hydroxyethoxy)phenyl]-N4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine7.3.647 R926720N4-(4-tert-Butylphenyl)-5-fluoro-N2-[2,3-dihydro-2-(carboxy)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.648 R926726N4-(4-tert-Butylphenyl)-N2-(3-carboxymethyleneoxyphenyl)-5-fluor-2,4-pyrimidinediamine7.3.649 R9267315-Fluoro-N2-[3-(carboxymethyleneoxy)phenyl]-N4-[4-(isopropoxy)phenyl]-2,4-pyrimidinediamine7.3.650 R926560N2,N4-Bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine7.3.651 R926483N2-(3-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.652 R945126N2-(3-Carboxymethyleneoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.653 R926238N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.654 R926564N2-(4-Carboxymethyleneoxyphenyl)-5-Fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.655 R926478N2-(2-Carboxybenzofuran-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.656 R926479N2-(2-Carboxyindol-5-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.657 R926481N4-(4-tert-Butylphenyl)-N2-(2-carboxybenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine7.3.658 R940280N4-(3-tert-Butylphenyl)-N2-[3-carboxymethyleneoxyphenyl]-5-fluoro-2,4-pyrimidinediamine7.3.659 R950190N2-(3-Carboxymethyleneaminophenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.660 R950230N2-(Carboxymethyleneaminophenyl)-5-fluoro-N4-[3-(2-hydroxyethyloxy)phenyl]-2,4-pyrimidinediamine 7.3.661 R9502315-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-hydroxyethylamino)]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.662 R950232N2-[3-(N-2-Aminoethylamino)carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylenoxy)phenyl]-2,4-pyrimidinediamine 7.3.663 R9502335-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-methylamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.664R950234 5-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-[N-(2-methylamino)ethylamino]carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.665 R950235N2-[3-[N-(2-N-Benzylamino)ethylamino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine 7.3.666 R9502365-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine 7.3.667R950237 N2-[3-(3-N,N-Dimethylaminopropyl)aminocarbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine 7.3.668 R950238N2-[3-[N-(2,3-Dihydroxypropyl)amino]carbonylmethyleneaminophenyl]-5-fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-2,4-pyrimidinediamine 7.3.669 R9502395-Fluoro-N4-[3-(2-hydroxyethylamino)phenyl]-N2-[3-(N-morpholinoethyleneamino)carbonylmethyleneaminophenyl]-2,4-pyrimidinediamine7.3.670 R926514 2,4-Bis[N-(L)-tyrosine methylester]-5-ethoxycarbonylpyrimidine 7.3.670 R9265135-Ethoxycarbonyl-2-methoxy-4-[N-(L)-tyrosine methyl ester]pyrimidine7.3.671 R926252N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.672 R926253N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine7.3.673 R926526 2,4-Bis[N-(L)-phenylalaninyl ethylester]-5-ethoxycarbonylpyrimidine 7.3.674 R926527 2,4-Bis[N-(L)-valinylethyl ester]-5-ethoxycarbonylpyrimidine 7.3.675 R9265285-Ethoxycarbonyl-N2-(3-hydroxyphenyl)-4-[N-(L)-phenylalanine ethylester]-2-pyrimidineamine 7.3.676 R926536N2-(3,4-Ethylenedioxyphenyl)-5-ethoxycarbonyl-4-[N-(L)-phenyl glycinylethyl ester)-2- pyrimidineamine 7.3.677 R926579N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.678 R926580N4-(4-tert-Butoxycarbonylmethyleneoxyphenyl)-N2-(4-methoxycarbonylmethyleneoxyphenyl)-5-methoxycarbonyl-2,4-pyrimidinediamine 7.3.679 R926583N4-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.680 R926584N2-(4-Carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.681 R9265355-Carboxy-N2-(3-hydroxyphenyl)-N4-[N-(L)-phenylglycine)-2-pyrimidineamine7.3.682 R9258565-Amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.683 R9258575-Amino-6-ethoxycarbonyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine7.3.684 R9258655-Amino-N2,N4-bis(ethoxycarbonylmethyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine7.3.685 R9265675-Amino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine 7.3.686 R926571N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine 7.3.687 R9265855-Allylaminocarbonylamino-N2,N4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl)-2,4-pyrimidinediamine 7.3.688 R926586N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylformyl)-2,4-5-pyrimidinetriamine 7.3.689 R926587N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine 7.3.690 R926588N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(cyclopentylaminocarbonylamino)-2,4-pyrimidinediamine 7.3.691 R926589N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(chloroacetylaminocarbonylamino)-2,4-pyrimidinediamine 7.3.692 R920669N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-trifluoro-2,4-pyridinediamine7.3.693 R920668N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-pyridyl)-2,4-pyrimidinediamine7.3.694 R920664N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-n-hexyloxyphenyl)-2,4-pyrimidinediamine7.3.695 R920666N2-(4-n-Butyloxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine7.3.696 R920670N4-(4-ethyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.697 R920671N4-(4-n-Butyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine7.3.698 R920672N4-(4-n-Hexyloxyphenyl)-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine7.3.699 R9208185-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.700 R920819N4-(3-Hydroxyphenyl)-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine7.3.701 R920820N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.702 [NEED RN4-(3-Benzyloxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-NO.] pyrimidineamine 7.3.703 R920917N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.704 [NEED RN4-(3-Benzyloxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-NO.] pyrimidineamine 7.3.705 R920910N4-(3-Hydroxyphenyl)-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.706 R9208615-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.707 R9208605-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.708 R920894N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.709 R920893N4-(3-Hydroxyphenyl)-5-methyl-N2-[4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidineamine 7.3.710 R925810N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine7.3.711 R925838 N2-[4-(N-Cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.712 R9258395-Ethoxycarbonyl-N4-(3-hydroxyphenyl)-N2-[4-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.713 R925840 N2-[4-(N-2,3-Dihydroxypropylamino)carbonylmethyleneoxyphenyl]-5-ethoxycarbonyl-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.714 R925841N2,N4-Bis[4-[N-(3-methoxybenzylamino)carbonylmethyleneoxy]phenyl]-5-bromo-2,4-pyrimidinediamine 7.3.715R925842 5-Bromo-N4-[4-[(N-cyclopropylmethylamino)carbonylmethyleneoxyphenyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.716 R9258435-Bromo-N2-(3-hydroxyphenyl)-N4-[4-(N-3-methoxybenzylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.717 R926698N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine7.3.718 R926016N2,N4-Bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.719 R926406N2-(3,4-Ethylenedioxyphenyl)-N4-(3,4-methylenedioxyphenylhydrazinyl)-5-fluoro-2-pyrimidineamine 7.3.720 R926566N2,N4-Bis(4-ethoxycarbonylmethylenedioxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine 7.3.721 R950202N2,N4-Bis[2-(methylthio)-1,3-benzothiaz-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.722 R950240 N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-(N-methyl)-piperazino)carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine7.3.723 R950241N4-[3-(2-Hydroxyethyleamino)phenyl]-N2-[3-(N-piperazino)-carbonylmethyleneaminophenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.724 R950251(±)-N4-(3-Aminophenyl)-5-fluoro-N2-(3-(3-carboxy-3-D,L-N-phtaloylamino)propylenecarbonylaminophenyl)-2,4-pyrimidinediamine7.3.725 R950255(±)-N4-(3-Aminophenyl)-5-fluoro-N2-[3-(3-carboxy-3-amino)propylenecarbonylaminophenyl]-2,4-pyrimidinediamine 7.3.726 R9265595-Methoxycarbonyl-N2,N4-bis[4-(N-pyrrolidino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.727 R925565N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyridinediamine7.3.728 R926799N2-(3-Ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-N4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine 7.3.729 R926811N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[N-2-(D)-(+)-biotinylethylamino]carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine7.3.730 R9267255-Fluoro-N4-(3-hydroxyphenyl)-N2[2-(N-methyl-N-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine 7.3.731 R926228N2,N4-Bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.732R908696N2-(3-chloro-4-methylbenzyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.733 R908697(±)-N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-phenylethyl)-2,4-pyrimidinediamine7.3.734 R925745N2-(3-Ethoxycarbonylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.735 R920394 N4-(3,4-Difluorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.736 R920396N4-(4-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.736.1 R920397N4-(3,4-Dichlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.737 R9203985-Fluoro-N4-(5-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.738 R9203995-Fluoro-N4-(6-methylpyridin-2-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.739 R920405N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine 7.3.740 R920406N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine 7.3.741 R9270165-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methylpyridin-2-yl)-2,4-pyrimidinediamine 7.3.742 R9204075-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine 7.3.743 R920408N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.744R920410 N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.745R926827 N4-(4-Ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.746 R926828N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.747R9268295-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methoxy-3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.748 R926832N4-(3-Chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.749 R9268335-Fluoro-N4-(3-methoxy-5-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.750R926834 5-Fluoro-N4-(3-hydroxy-4-methoxyphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]- 2,4-pyrimidinediamine 7.3.751 R9268355-Fluoro-N4-(4-methoxy-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.752R926838 5-Fluoro-N4-(4-fluoro-3-trifluoromethylphenyl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.753R926839N4-(3-Chloro-4-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.754 R926840N4-(2-Chloro-5-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.755 R926830N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-isopropylamino)carbonylmethyleneoxyphenyl]- 2,4-pyrimidinediamine 7.3.756 R926848N2-[3-(N-Cyclopropylamino)carbonylmethyleneoxyphenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.757 R926851N4-(4-Cyano-3-methylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4- pyrimidinediamine 7.3.758 R9268555-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.3.759 R9268565-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(N-methylphthalimido-4-yl)-2,4-pyrimidinediamine 7.3.760 R926859N4-(2,5-Dimethoxy-4-chlorophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.761 R9268625-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.762 R9268705-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.3.763 R926871N4-[3-(2-(3-Chlorophenyl)-1,3,4-oxadiazol-5-yl)phenyl]-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.764R9268795-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine 7.3.765 R9268805-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-[4-trifluoromethylphenyl]-2,4-pyrimidinediamine 7.3.766 R926881N4-(4-Chloro-3-trifluoromethylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.767R9268835-Fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine 7.3.768 R9268865-Fluoro-N4-(2-methoxypyridin-5-yl)-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine 7.3.769 R9270235-Fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.770R920404N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.771 R927042N4-(4-Chloro-3-methoxyphenyl))-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine 7.3.772 R920411N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.773 R9268665-Fluoro-N2-(3-hydroxyphenyl)-N4-[3-(3-phenyl-1,3,4-oxadiazol-5-yl)phenyl]-2,4-pyrimidinediamine 7.3.774 R926794N4-(3,4-Difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.775 R9268855-Fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine7.3.776 R926887N4-(2,6-Dimethoxypyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.777 R9270175-Fluoro-N2-(3-hydroxyphenyl)-N4-(5-methylpyridin-2-yl)-2,4-pyrimidinediamine7.3.778 R927018N4-(6-Chloropyridin-3-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.779 R9270195-Fluoro-N2-(3-hydroxyphenyl)-N4-(quinolin-6-yl)-2,4-pyrimidinediamine7.3.780 R927020N4-(5-Chloropyridin-2-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.781 R926860N4-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine7.3.782 R927026N4-(4-Chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine7.3.783 R927027N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine7.3.784 R9268635-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.785 R926857N2-(4-Chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.786 R926846N2-(3-Bromo-5-trifluorophenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.787 R9268415-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine7.3.788 R9268425-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine7.3.789 R9268315-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine7.3.790 R926844N2-(3-Chloro-4-trifluoromethylphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.791 R9268435-Fluoro-N4-(3,4-ethylenedioxyphenyl)-N2-[3-(tetrazol-5-yl)phenyl]-2,4-pyrimidinediamine7.3.792 R926845N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine7.3.793 R926847N2-[5-(N-Aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine 7.3.794 R926874N2-[3-(2-Ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.795 R926836N2,N4-Bis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.796R926837N2-(3-Boronylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.797 R927030(±)-N4-(3,4-Difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.798 R927024(±)-N4-(4-Chlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.799 R927031(±)-N4-(3,4-Dichlorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.800 R927032(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-2,4-pyrimidinediamine 7.3.801 R927025(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.802R927028(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-N4-(3-trifluorophenyl)-2,4-pyrimidinediamine 7.3.803 R927029(±)-N2-(2,3-Dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.804 R927035(±)-N4-(3,4-Difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine 7.3.805 R927036(±)-N4-(4-Chlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.806 R927037(±)-N4-(3,4-Dichlorophenyl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.807 R927038(±)-N4-(2,6-Dimethoxypyridin-3-yl)-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.808 R927039(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-[2-(2-hydroxyethyleneoxy)pyridin-5-yl]-2,4-pyrimidinediamine 7.3.809 R927040(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine 7.3.810 R927041(±)-N2-[2,3-Dihydro-(N-methylamino)carbonylbenzofuran-5-yl]-N4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.811R926238N2-(4-Carboxymethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.812 R920395N4-(1,4-Benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Hydrogen Chloride Salt 7.3.813 R926826N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine Trifluoro Acetic Acid Salt 7.3.814 R9267525-Fluoro-N4-[(1H)-indol-6-yl]-N2-[4-methoxy-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.815 R9267535-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.816 R9267545-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.817 R9267555-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.818 R926756N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine7.3.819 R9267575-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.820 R926758N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.821R926759 5-Fluoro-N4-(3-hydroxy-4-methylphenyl)-N2-[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.822R926760 5-Fluoro-N2,N4-bis[4-methyl-3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4- pyrimidinediamine 7.3.823 R9267615-Fluoro-N4-(3-hydroxyphenyl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine7.3.824 R926762N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine7.3.825 R926763N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-2,4-pyrimidinediamine7.3.826 R9268905-Fluoro-N2-(3,5-dichloro-4-hydroxyphenyl)-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.827 R926891N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.828 R9268925-Fluoro-N4-(3-fluoro-4-methoxyphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.829 R926893N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(3-hydroxy-5-methylphenyl)-2,4-pyrimidinediamine7.3.830 R926894N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-fluoro-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.831 R926895N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.832 R926896N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(5-methoxy-2-methylphenyl)-2,4-pyrimidinediamine7.3.833 R926897N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(2-fluoro-5-methylphenyl)-2,4-pyrimidinediamine7.3.834 R926898N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine7.3.835 R926899N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine7.3.836 R926900N4-[3-(Benzothiazol-2-yl)-4-chlorophenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl)-2,4-pyrimidinediamine 7.3.837R9269025-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine 7.3.838 R9269035-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(methoxycarbonyl)-(1H)-indol-6-yl])-2,4-pyrimidinediamine7.3.839 R9269045-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-2,4-pyrimidinediamine 7.3.840 R926905N4-[3-[[4-(Ethoxycarbonyl)pipiridino]methyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl-2,4-pyrimidinediamine 7.3.841R926906N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.842 R926907N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.843 R926908N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine 7.3.844 R926909N2-[3-(Ethoxycarbonyl-1,1-dimethylmethyleneoxy)phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine 7.3.845 R9269135-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.846 R9269145-Fluoro-N4-(1,2,3,4-tetrahydroisoquin-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.847R926915N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[3-[(N-methylamino)carbonyl-1,1-dimethylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.848 R9269175-Fluoro-N4-[3-[(N-allylamino)carbonyloxy]phenyl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.849R9269165-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-[3-[[(N-isopropylamino)carbonyl]-N-isopropylamino)carbonyloxy]phenyl]-2,4-pyrimidinediamine 7.3.850 R926918N4-[3-[[N-(Ethoxycarbonylmethyl)amino]carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.851R926919 N4-[3-[(N-(Ethylamino)carbonyloxy]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.852R9269225-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(4-methyl-3-trifluoromethylphenyl)-2,4-pyrimidinediamine 7.3.853 R9269235-Fluoro-N4-(4-fluoro-3-methylphenyl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.854 R9269255-Fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-trifluoromethylthiophenyl)-2,4-pyrimidinediamine 7.3.855 R926926N2-[3,5-Bis(methoxycarbonylmethyleneoxy)phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.856 R9269275-Fluoro-N2-[3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.857 R926928N2-[3-[(N-Ethylamino)carbonyloxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.858 R926929 5-Fluoro-N2-[3-hydroxy-5-[(N-methylamino)carbonylmethyleneoxy]phenyl]-N4-(3-hydroxyphenyl)- 2,4-pyrimidinediamine7.3.859 R926930N2-[3,5-Bis[(N-methylamino)carbonylmethyleneoxy]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.860 R9269315-Fluoro-N4-[(1H)-indol-5-yl]-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4- pyrimidinediamine 7.3.861 R9269325-Fluoro-N2-(3-hydroxyphenyl)-N4-[(1H)-indol-5-yl]-2,4-pyrimidinediamine7.3.862 R9269335-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine7.3.863 R9269345-Fluoro-N4-[(1H)-indol-6-yl]-N2-[3-(N-morpholinocarbonyl)phenyl]-2,4-pyrimidinediamine7.3.864 R926935N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-[(1H)-indol-6-yl]-2,4-pyrimidinediamine 7.3.865 R9269365-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine7.3.866 R9269375-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-[(N-propylamino)carbonyl]phenyl]-2,4-pyrimidinediamine7.3.867 R9269385-Fluoro-N4-(3-hydroxyphenyl)-N2-[3-(N-morphonlinocarbonyl)phenyl]-2,4-pyrimidinediamine7.3.868 R926939N2-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.869 R926940N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.870 R926941N4-[3-[[4-(Ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.8717.3.872 R926942N4-(1-Ethoxy-1,2,3,4-tetrahydronaphthalen-7-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.873 R9269435-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.874 R9269445-Fluoro-N4-(3,4-dihydronaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.875 R926945N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.876 R926946N2,N4-Bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.877 R9269475-Fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.878R9269485-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.879R9269495-Fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-N2-[3-[(N-methylamino)carbonylmethyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.880R926950 N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2-(methoxycarbonyl)benzofuran-5-yl]-2,4- pyrimidinediamine 7.3.881 R926951N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.882 R926953N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.883 R926954N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.884R926955N4-(3-Chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-2,4-pyrimidinediamine 7.3.885 R9269565-Fluoro-N2-[2,3-dihydro-2-[(N-methylamino)carbonyl]benzofuran-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.886 R925809N2,N4-Bis(3-phenylphenyl)-2,4-pyrimidinediamine 7.3.887 R9401102-Dimethylamine-5-fluoro-N4-(thyrosinyl methyl ester) pyrimidine 7.3.888R9402995-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-aminocarbonylphenyl)-2,4-pyrimidinediamine 7.3.889 R9403005-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine 7.3.890 R9403015-Fluoro-N4-(3-hydroxyphenyl)-N2-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine7.3.891 R9403045-Fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine7.3.892 R9403065-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine 7.3.893 R940307(R)-N2-[3-(dihydroxypropylaminocarbonylmethyleneoxy)-phenyl]-5-fluoro-N4-(3-isopropylphenyl)-2,4-pyrimidinediamine 7.3.894 R940308N4-(3-tert-Butylpheny)-5-fluoro-N2-[3-(1,1-dimethyl-2-hydroxyethylaminocarbonylmethyleneoxy)-phenyl]-2,4-pyrimidinediamine 7.3.895 R940309N4-(3-Aminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.896 R940311N4-[3-(2-(N4-(3-aminomethylenephenyl)-5-fluoro-4-pyrimidineamine)-N-methylaminomethylene)-phenyl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidineamine7.3.897 R9403125-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine 7.3.898 R9403145-Fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine 7.3.899 R940316N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-morpholinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine 7.3.900 R940317N4-(3-N-methylaminomethylenephenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.901R940318N2-(3-Chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N4-[3-(N-piperazinomethylene)-4-methoxyphenyl]-2,4-pyrimidinediamine 7.3.902 R940319N4-(3-(N-tert-Butoxycarbonyl-N-iso-propylaminomethylene)-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonyl methyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.903R940321N4-(3-N,N-Dimethylaminomethylene-4-methoxyphenyl)-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.904R940323N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.905R940337N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.906R940338N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine 7.3.907 R940343N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.908R940345N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-7-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.909R940346N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.910 R940347N4-[(2,2-Dimethyl-4H-5-pyrido[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.911R940348N4-[3-Dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo[1,4]oxazin-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.912 R940349N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.913 R940350N2,N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.914 R940351N2-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-N4-[(2,2-dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.915 R940352N2,N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.916 R940353N4-[(2,2-Difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.917 R940354N4-[(2,2-Dimethyl-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.918 R950244N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine7.3.919 R950245N4-(3-N,N-Diacetylaminophenyl)-N2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine 7.3.920 R950246N4-(3-N-Acetylaminophenyl)-N2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine 7.3.921 R950247N2,N4-Bis(3-N,N-diacetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine7.3.922 R950261N4-(3-Nitrophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.923 R950262N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HCl salt 7.3.924 R950264N4-(3-Aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamineN4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.925R950264N4-(3-Bis-N-methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.926 R950265N4-(3-N-Hydroxyethylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.927 R950266N4-(3-Bis(N-hydroxyethyl)aminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.928R950267N4-(3-N-Methylaminophenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.929 R950290N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.930 R950291N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-hydroxycarbonylmethyleneoxypheyl]-2,4-pyrimidinediamine 7.3.931 R950293N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.932 R950294N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.933 R950295N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.934 R950296N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.935R950344 N4-(4-Hydroxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.936R950345 N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.937R950346 N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.938R950347N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.939 R950348N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.940R950349N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.941R950356N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.942R950368 N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.943R950371N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamio)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.944 R950372N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.945 R950373N4-(3-Methyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.946 R950374N4-(3-Phenyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.947 R950376N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.948R950377 N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.949 R950378N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.950 R950379N2,N4-Bis(3-methyloximephenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.951R950380 N2,N4-Bis(3-phenyloximephenyl)-5-fluoro-2,4-pyrimidinediamine7.3.952 R950381N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.953 R950382N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.954R950383 N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.955R950385N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.956 R950386N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.957R950388N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.958 R950389N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.959R950391N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.960 R950392N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.961R950393N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.962R945236N4-[2,4-Dihydro-1-oxo-4H-imidazo[2,1-c][1,4]benzoxazin-8-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.963 R9452375-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-oxo-1,2,3,6-tetrahydropyrimido[2,1-c][1,4]benzoxazin-9-yl]-2,4-pyrimidinediamine 7.3.964 R9452425-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-7-yl]-2,4-pyrimidinediamine 7.3.965 R9452635-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-7-yl]-2,4-pyrimidinediamine 7.3.966 R9452805-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-2,4-pyrimidinediamine 7.3.967 R9452995-Fluoro-N2-(3-methylaminocarbonylmethyleneoxyphenyl)-N4-[2H-pyrido[3,2-b]-1,4-oxazin-6-yl]-2,4-pyrimidinediamine R908698 R908698N4-(1,4-Benzoxazin-3-on-7-yl))-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.969 R908699N2-(1,4-Benzoxazin-3-on-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.970 R908701 N4-(1,4-Benzoxazine-3-on-7-yl)-5-fluoro-N2-((N-methylacetamido-2)-3-phenoxy)-2,4- pyrimidinediamineN4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methyl acetamido-2)-3-phenoxy)]-2,4-pyrimidinediamine 7.3.971 R908701R908701)N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-[(N-methylacetamido-2)-3-phenoxy)]-2,4- pyrimidinediamine 7.3.972 R908702N4-(1,4-Benzoxazine-3-on-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.973 R9087035-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazine-3-on-6-yl)-2,4-pyrimidinediamine7.3.974 R9087045-Fluoro-N4-(3-hydroxyphenyl)-N2-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine7.3.975 R908706 5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamineN2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.976 R908706N2-(1,4-Benzoxazin-7-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.977 R9087075-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-7-yl)-2,4-pyrimidinediamine7.3.978 R908709 5-Fluoro-N4-(3-hydroxyphenyl)N2-(N-Methyl-1,4-benzoxazine-3-on-7-yl)-2,4-pyrimidinediamine5-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine7.3.979 R9087095-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-6-yl)-2,4-pyrimidinediamine7.3.980 R9087345-Fluoro-N2-(3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamineN2-(N- Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine 7.3.981 R908734N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine 7.3.982 R908712(+/−)-5-Fluoro-N2-[(N-methylacetamido-2)-3-phenoxy]-N4-(2-methyl-1,4-benzoxazin-6-yl)-2,4-pyrimidinediamine 7.3.983 R908734N2-(N-Ethylcarbonylmethyleneoxy-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-hydroxyphenyl)phenyl]pyrimidinediamine 7.3.984 R909255N4-(1,4-Benzoxazin-6-yl)-N2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoropyrimidinediamine7.3.985 R9092595-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-6-yl)pyrimidinediamine 7.3.986 R9092605-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-[6-(N-methyl-1,4-benzoxazin-3-onyl)]pyrimidinediamine 7.3.987 R9092615-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)]-2,4-pyrimidinediamine 7.3.988 R909263(+/−)-5-Fluoro-N4-(3-hydroxyphenyl]-N2-(2-methyl-1,4-benzothiazin-3-on-6-yl)pyrimidinediamine7.3.989 R9092645-Fluoro-N2-[3-hydroxyphenyl)-N4-(N-methyl-1,4-benzoxazin-3-on-7-yl)-2,4-pyrimidinediamine7.3.990 R909265N4-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]pyrimidinediamine 7.3.991 R909266N4-(1,4-Benzoxazin-7-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.992 R909267N2-(3-Ethylcarboxy-4H-imidazo[5,1-c]-1,4-benzoxazin-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)pyrimidinediamine 7.3.993 R909268N2-(1,4-Benzoxazin-3-on-6-yl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.994 R909290N2-[3-(N,N-Dimethylaminocarbonylmethyleneoxy)phenyl]-N4-(1,4-benzoxazin-6-yl)-5-fluoro--2,4-pyrimidinediamine 7.3.995 R909292N4-(4N-Carboxamidino-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.996R909308N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-N2-[3-ethoxycarbonylmethyleneoxy)phenyl]-5-fluoro-2,4-pyrimidinediamine 7.3.997 R909309N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.998R909309 N4-(3,3-Dimethyl-1,4-benzoxazin-6-yl)-5-fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.999R935221N4-(2,4-Diiodo-3-hydroxypheny)-5-fluoro-N2-(3-iodo-1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine 7.3.1000 R9352225-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1001 R935223N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1002 R9352245-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1003 R935225N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(N-methylaminocarbonyl)methyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1004 R9352375-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1005 R935238N2,N4-Bis[1-(2-hydroxyethyl)indazoline-6-yl]-5-fluoro-2,4-pyrimidinediamine7.3.1006 R9352395-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1007 R935240N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(N-methylaminocarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1008 R9352425-Fluoro-N2-(4-isopropoxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1009 R935248N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-hydroxyethyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1010 R935249N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1011 R9352505-Fluoro-N2-(3-hydroxyphenyl)-N4-[1-(methoxycarbonyl)methyl-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1012 R9352515-Fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1013 R935252N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1014 R9352535-Fluoro-N4-(3-hydroxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1015 R9352555-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.1016 R9352565-Fluoro-N2-[1-(2-hydroxyethyl)indazoline-5-yl]-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.1017 R935258N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1018 R9352595-Fluoro-N4-[1-(2-hydroxyethyl)indazoline-5-yl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine7.3.1019 R935261N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1020 R9352625-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1021 R935263N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-2,4-pyrimidinediamine 7.3.1022 R935264N2-(3-Chloro-4-hydroxy-3-methylphenyl)-5-fluoro-N4-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1023 R9352665-Fluoro-N4-(indazoline-5-yl)-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.1024 R935267N2-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N4-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1025 R9352685-Fluoro-N2-(3-hydroxyphenyl)-N4-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1026 R935269 5-Fluoro-N4-(indazoline-5-yl)-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-2,4- pyrimidinediamine 7.3.1027 R9352705-Fluoro-N4-(indazoline-5-yl)-N2-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1028 R9352715-Fluoro-N4-[4H-imidazo[2,1-c][1,4]-benzoxazin-8-yl]-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.1029R9352765-Fluoro-N2-(4-isopropoxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1030 R935277N2-(3,4-Ethylenedioxyphenyl)-5-Fluoro-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1031 R9352785-Fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine7.3.1032 R9352795-Fluoro-N4-(indazoline-5-yl)-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamine 7.3.1033 R9352805-Fluoro-N2-[3-(methoxycarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine 7.3.1034 R9352815-Fluoro-N2-[3-(N-methylaminocarbonylmethyleneoxy)phenyl]-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine 7.3.1035 R935286N2-[1-(2-ethoxycarbonylethyl)indazoline-6-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.1036 R935287N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1037 R935288N2-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1038 R935289N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.1039 R9352905-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.1040 R9352915-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylamino)carbonyl]ethyl-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1041 R935292N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.1042 R9352935-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine7.3.1043 R9352945-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1044 R935295N4-[1-(2-Ethoxycarbonylethyl)indazoline-6-yl]-5-fluoro-N2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine 7.3.1045 R9352975-Fluoro-N4-[2-(N-methylaminocarbonyl)benzofuran-5-yl]-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1046 R9352985-Fluoro-N4-(4-isopropoxyphenyl)-N2-(2-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.1047 R9352995-Fluoro-N4-(3-hydroxyphenyl)-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine7.3.1048 R935300N4-(3,4-Ethyelenedioxyphenyl)-5-fluoro-N2-(2-methy-indazoline-5-yl)-2,4-pyrimidinediamine7.3.1049 R935301N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.1050 R935302N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1051 R935303N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine 7.3.1052 R9353045-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine7.3.1053 R9353055-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1054 R935306N4-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine 7.3.1055 R9353075-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine7.3.1056 R9353085-Fluoro-N4-(2-hydroxymethylbenzofur-5-yl)-N2-[1-(3-hydroxypropyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1057 R935309N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1058 R9353105-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2(N-methylaminocarbonyl)ethyl]-indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1059 R935320N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1060 R9353215-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1061 R9353225-Fluoro-N4-(4-isopropoxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine7.3.1062 R935323N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N4-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine7.3.1063 R935324 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-6-yl]-2,4-pyrimidinediamine7.3.1064 R935336N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1065 R9353375-Fluoro-N4-(3-hydroxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1066 R9353385-Fluoro-N4-(4-isopropoxyphenyl)-N2-[2-(2-methoxy-4-carbomethoxybenzyl)indazoline-6-yl]-2,4-pyrimidinediamine 7.3.1067 R935339N4-(3,4-Ethylenedioxyphenyl)-5-fluoro-N2-[1-[2-methoxy-4-o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine7.3.1068 R935340 5-Fluoro-N4-(3-hydroxyphenyl)-N2-[1-[2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl]indazoline-5-yl]-2,4-pyrimidinediamine7.3.1069 R935351N4-(4-Chlorophenyl)-5-fluoro-N2-(1-methyl-indazoline-5-yl)-2,4-pyrimidinediamine7.3.1070 R935352N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1071 R935353N4-(4-Chlorophenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine7.3.1072 R935354N4-(3-Chloro-4-trifluoromethoxy-phenyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.1073 R935355N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine7.3.1074 R9353565-Fluoro-N2-(1-methylindazoline-5-yl)-N4-(3-trifluoromethoxypheny)-2,4-pyrimidinediamine7.3.1075 R935357N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine 7.3.1076 R935358N4-(3,4-Difluorophenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine7.3.1077 R935359N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine 7.3.1078 R935360N2-[1-(2-Ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine 7.3.1079 R9353615-Fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine 7.3.1080 R9353625-Fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine 7.3.1081 R9353635-Fluoro-N2-(indazoline-6-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine7.3.1082 R9353645-Fluoro-N2-(indazoline-5-yl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine7.3.1083 R935365N4-(4-Chlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1084 R935366N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1085 R9353675-Fluoro-N4-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine 7.3.1086 R935368N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1087 R935369N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine7.3.1088 R935370N4-(3-Chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1089 R935371N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1090 R935372N4-(3,4-Dichlorophenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1091 R935373N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1092 R935374N4-(3,4-Difluoromethylendioxyphenyl)-5-fluoro-N2-(indazoline-6-yl)-2,4-pyrimidinediamine7.3.1093 R935375N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(1-methylindazoline-5-yl)-2,4-pyrimidinediamine7.3.1094 R935376N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-(indazoline-5-yl)-2,4-pyrimidinediamine7.3.1095 R935377N4-(6-Chloro-3-pyridyl)-N2-[1-(2-ethoxycarbonylethyl)indazoline-5-yl]-5-fluoro-2,4-pyrimidinediamine 7.3.1096 R935378N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-[2(N-methylaminocarbonyl)ethyl]indazoline-5-yl]-2,4-pyrimidinediamine 7.3.1097 R935379N4-(6-Chloro-3-pyridyl)-5-fluoro-N2-[1-(3-hydroxypropyl)indazoline-5-yl]-2,4-pyrimidinediamine7.3.1098 R935380N4-6-Dimethoxy-3-pyridyl)-5-fluoro-N2-[1-methylindazoline-5-yl]-2,4-pyrimidinediamine7.3.1099 R008951 N2,N4-Bis(3-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine R067962 R026209 7.3.1099R008952 N2,N4-Bis (2,5-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamineR067963 7.3.1099 R008953 N2,N4-Bis(3,4-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamine R067964 7.3.1099R008955 N2,N4-Bis (2-methoxyphenyl)-5-Fluoro-2,4-pyrimidinediamineR081166 7.3.1099 R008956 N2,N4-Bis(2,4-dimethylphenyl)-5-Fluoro-2,4-pyrimidinediamine R070791 7.3.1099R008958 N2,N4-Bis (3-bromophenyl)-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R088814 N2,N4-Bis(4-methoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine R926017 7.3.1099R088815 N2,N4-Bis (2-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R091880 N2,N4-Bisphenyl-5-Fluoro-2,4-pyrimidinediamine 7.3.1099R092788 N2,N4-Bis (3-methylphenyl)-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R920846N2-(3-hydroxyplhenyl)-N4-[4-(tetrazol-5-yl)methoxyphenyl)]-5-trifluoromethyl-2,4-pyrimidinediamine 7.3.1099 R070153 N2,N4-Bis(4-chlorophenyl)-5-Fluoro-2,4-pyrimidinediamine 7.3.1099 R070790N2,N4-Bis (4-ethoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine R9260367.3.1099 R926736N2-(3,4-ethylenedioxyphenyl)-N4-[3-(N-methylaminomethyleneoxyphenyl)]-5-trifluoromethyl-2,4-pyrimidinediamine andN2-[3-(N-methylaminomethyleneoxyphenyl)]-N4-(3,4-ethylenedioxyphenyl)-5-trifluoromethyl-2,4-pyrimidinediamine 7.3.1099 R935117 N2,N4-Bis(3-carboxymethylphenyl)-5-Fluoro-2,4-pyrimidinediamine 7.3.1099 R926593N2,N4-Bis (2-methoxycarbonylindol-6-yl)-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R950189N2-(3,4-ethylenedioxyphenyl)-N4-methyl-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R950216N2-(3-hydroxyphenyl)-N4-(3-ethoxymethyleneoxyphenyl)-5-Fluoro-2,4-pyrimidinediamine7.3.1099 R950218N2-(3-hydroxyphenyl)-N4-[3-(N-methylamino)carbonylmethyleneaminophenyl]-5-Fluoro-2,4-pyrimidinediamine 7.3.1100 7.3.1101 R926408N2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine 7.3.1101 R926409N2,N4,N6-Tris(3-hydroxyphenyl)-2,4,6-pyrimidinetriamine 7.3.1102 R926411N2,N4-Bis(4-methoxycarbonylmethyleneoxyphenyl)-6-chloro-2,4-pyrimidinediamine7.3.1103 R926245N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-chloro-2,4-pyrimidinediamine7.3.1103 R926516N2,N4,N6-Tris(3,4-ethylenedioxyphenyl)-2,4,6-pyrimidinetriamine 7.3.11047.3.1105 R9265556-Chloro-N2-(4-ethoxycarbonylmethyleneoxyphenyl)-N4-(methoxycarbonylmethyl)-2,4-pyrimidinediamine 7.3.1106 R926467N2,N4-Bis(3,4-ethylenedioxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine7.3.1107 R926569N2,N4-Bis(4-ethoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine7.3.1108 R926576N2,N4-Bis(4-tert-butoxyoxycarbonylmethyleneoxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine7.3.1109 Reaction of 2,4,5,6-tetrachloropyrimidine with 3-hydroxyaniline7.3.1109 R926590 N4-(3-Hydroxyphenyl)-2,5,6-trichloro-4-pyrimidineamine7.3.1109 R926591N2,N4-Bis(3-hydroxyphenyl)-5,6-dichloro-2,4-pyrimidinediamine 7.3.1109R926592 N4,N6-Bis(3-hydroxyphenyl)-2,5-dichloro-4,6-pyrimidinediamine7.3.1110 R926595N2,N4-Bis(3-hydroxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine7.3.1111 R926475N2,N4-Bis(3,4-ethyelenedioxyphenyl)-5-chloro-6-thiomethyl-2,4-pyrimidinediamine7.3.1112 R926530 6-Chloro N4-(3-hydroxyphenyl)-4-pyrimidineamine7.3.1113 R925784N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine7.3.1114 R925785N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(2-furanyl)-2,4-pyrimidinediamine7.3.1115 R925786N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-chlorophenyl)-2,4-pyrimidinediamine7.3.1116 R925787N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(3-chlorophenyl)-2,4-pyrimidinediamine7.3.1117 R925813N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-methoxycarbonylphenyl)-2,4-pyrimidinediamine7.3.1118 R925816N2,N4-Bis(3,4-ethylenedioxyphenyl)-5-(4-hydroxyphenyl)-2,4-pyrimidinediamine7.3.1119 R925783N2,N4-Bis(3-hydroxyphenyl)-5-phenyl-2,4-pyrimidinediamine 7.3.1120R925788N2,N4-Bis(3-hydroxyphenyl)-5-(3,4-methylenedioxyphenyl)-2,4-pyrimidinediamine7.3.1121 R925811N2,N4-Bis(3,4-ethylenedioxyphenyl)-6-phenyl-2,4-pyrimidinediamine7.3.1122 R925812N2,N4-Bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine 7.3.1123R926747N2-(3-Aminocarbonylmethyleneoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.1124 R926461N2,N4-Bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine 7.3.1125R9451695-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)methyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1126 R9267025-Fluoro-N4-(3-hydroxyphenyl)-N2-[4-[(4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy]phenyl]-2,4-pyrimidinediamine 7.3.1127 R950290N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1128 R950291N4-(3-Hydroxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-hydroxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1129 R950293N4-(3-Methoxycarbonyl-4-hydroxyphenyl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1130 R950294N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-ethoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1131 R950295N4-(4-Methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-methoxycarbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1132R950296N4-(4-Ethoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1133R950344 N4-(4-Hydroxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1134R950345N4-(2,3-Dihydro-4-benzypyranon-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1135 R950346N4-(4-Methoxycarbonylethyleneoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1136R950347N4-(4-Hydroxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1137 R950348N4-(2,3-Dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1138R950349N4-(4-Hydroxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1139R950356N4-(2,3-Dihydro-4-O-methyloxime-benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1140R950368 N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1141R950371N4-(3-Methylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1142 R950372N4-(3-Phenylcarbonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1143 R950373N4-(3-Methyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1144 R950374N4-(3-Phenyloximephenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1145 R950376N2,N4-Bis(3-methylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.1146 R950377N2,N4-Bis(3-phenylcarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.1147 R950378N2,N4-Bis(2,3-dihydro-4-benzypyranon-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.1148 R950379N2,N4-Bis(3-methyloximephenyl)-5-fluoro-2,4-pyrimidinediamine 7.3.1149R950380 N2,N4-Bis(3-phenyloximephenyl)-5-fluoro-2,4-pyrimidinediamine7.3.1150 R950381N2,N4-Bis(2,3-dihydro-4-oxime-benzypyran-6-yl)-5-fluoro-2,4-pyrimidinediamine7.3.1151 R950382N4-(4-Acetyloxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1152R950383N4-(4-Azido-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1153 R950385N4-(4-Benzypyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1154 R950386N4-(3-Hydroxymethylen-4-methoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1155R950388N4-(3-Amino-4-ethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1156 R950389N4-(4-Ethoxy-3-hydroxysulfonylphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1157 R950391N2,N4-Bis(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine7.3.1158 R950392 N4-(3-Methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1159R950393N4-(4-Acetylamino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine 7.3.1160R950399 N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HCl salt7.3.1161 R950400N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine succinicacid salt 7.3.1162 R950401N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine maleicacid salt 7.3.1163 R950402N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine fumaricacid salt 7.3.1164 R950403N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine citricacid salt 7.3.1165 R950404N4-(4-Amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine HNO₃ salt

7.4 Synthesis of Prodrugs

Exemplary prodrugs according to structural formula (II) were synthesizedas described below.

7.4.1N-2(4)-Acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine(R926233)

A mixture ofN2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine,acetyl chloride (4 equivalents), pyridine (4 equivalents) in CH₂Cl₂ wasstirred at room temperature for 48 h. After an aqueous work up theresidue was chromatographed on silica gel to giveN-2(4)-acetyl-N2,N4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine.¹H NMR (CDCl₃): δ 8.23 (d, 1H, J=5.4 Hz), 7.03 (d, 1H, J=2.4 Hz),7.90-7.80 (m, 3H), 6.76 (m, 2H), 4.28 (bs, 4H), 2.10 (s, 3H); ¹⁹F NMR(CDCl₃): −42125; LCMS: ret. time: 27.94 min.; purity: 99%; MS (m/e): 439(MH⁺).

7.4.2N2,N4-Bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950244)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN2,N4-bis(3-N-acetylaminophenyl)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 17.03 min.; purity: 87.0%; MS (m/e): 478.89 (MH⁺).

7.4.3N4-(3-N,N-Diacetylaminophenyl)-N-2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950245)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-(3-N,N-diacetylaminophenyl)-N-2-(3-N-acetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 19.27 min.; purity: 92.6%; MS (m/e): 521.01 (MH⁺).

7.4.4N4-(3-N-Acetylaminophenyl)-N-2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine(R950246)

N2,N4-Bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine,dimethylaminopyridine (DMAP) and acetic anhydride were refluxed inpyridine for 1 hour. The mixture was cooled to room temperature,concentrated, and the residue was subjected to column chromatography onsilica gel (CHCl₃:Acetone, 2:1) to giveN4-[3-N-acetylaminophenyl]-N-2-(3-N,N-diacetylaminopheny)-5-fluoro-N2,N4-pyrimidinediacetylamine.LCMS: ret. time: 18.89 min.; purity: 83.0%; MS (m/e): 520.97 (MH⁺).

7.5 The 2,4-Pyrimidinediamine Compounds of the Invention Inhibit FcεRIReceptor-Mediated Degranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit IgE-induced degranulation was demonstrated in a variety ofcellular assays with cultured human mast cells (CHMC) and/or mouse bonemarrow derived cells (BMMC). Inhibition of degranulation was measured atboth low and high cell density by quantifying the release of the granulespecific factors tryptase, histamine and hexosaminidase. Inhibition ofrelease and/or synthesis of lipid mediators was assessed by measuringthe release of leukotriene LTC4 and inhibition of release and/orsynthesis of cytokines was monitored by quantifying TNF-α, IL-6 andIL-13. Tryptase and hexosaminidase were quantified using fluorogenicsubstrates as described in their respective examples. Histamine, TNFα,IL-6, IL-13 and LTC4 were quantified using the following commercialELISA kits: histamine (Immunotech #2015, Beckman Coulter), TNFα(Biosource #KHC3011), IL-6 (Biosource #KMC0061), IL-13 (Biosource#KHC0132) and LTC4 (Cayman Chemical #520211). The protocols of thevarious assays are provided below.

7.5.1 Culturing of Human Mast and Basophil Cells

Human mast and basophil cells were cultured from CD34-negativeprogenitor cells as described below (see also the methods described incopending U.S. application Ser. No. 10/053,355, filed Nov. 8, 2001, thedisclosure of which is incorporated herein by reference).

7.5.1.1 Preparation of STEMPRO-34 Complete Medium

To prepare STEMPRO-34 complete medium (“CM”), 250 mL STEMPRO-34™ serumfree medium (“SFM”; GibcoBRL, Catalog No. 10640) was added to a filterflask. To this was added 13 mL STEMPRO-34 Nutrient Supplement (“NS”;GibcoBRL, Catalog No. 10641) (prepared as described in more detail,below). The NS container was rinsed with approximately 10 mL SFM and therinse added to the filter flask. Following addition of 5 mL L-glutamine(200 mM; Mediatech, Catalog No. MT 25-005-CI and 5 mL 100×penicillin/streptomycin (“pen-strep”; HyClone, Catalog No. SV30010), thevolume was brought to 500 mL with SFM and the solution was filtered.

The most variable aspect of preparing the CM is the method by which theNS is thawed and mixed prior to addition to the SFM. The NS should bethawed in a 37° C. water bath and swirled, not vortexed or shaken, untilit is completely in solution. While swirling, take note whether thereare any lipids that are not yet in solution. If lipids are present andthe NS is not uniform in appearance, return it to the water bath andrepeat the swirling process until it is uniform in appearance. Sometimesthis component goes into solution immediately, sometimes after a coupleof swirling cycles, and sometimes not at all. If, after a couple ofhours, the NS is still not in solution, discard it and thaw a freshunit. NS that appears non-uniform after thaw should not be used.

7.5.1.2 Expansion of CD34+ Cells

A starting population of CD34-positive (CD34+) cells of relatively smallnumber (1-5×10⁶ cells) was expanded to a relatively large number ofCD34-negative progenitor cells (about 2-4×10⁹ cells) using the culturemedia and methods described below. The CD34+cells (from a single donor)were obtained from Allcells (Berkeley, Calif.). Because there is adegree of variation in the quality and number of CD34+cells thatAllcells typically provides, the newly delivered cells were transferredto a 15 mL conical tube and brought up to 10 mL in CM prior to use.

On day 0, a cell count was performed on the viable (phase-bright) cellsand the cells were spun at 1200 rpm to pellet. The cells wereresuspended to a density of 275,000 cells/mL with CM containing 200ng/mL recombinant human Stem Cell Factor (“SCF”; Peprotech, Catalog No.300-07) and 20 ng/mL human flt-3 ligand (Peprotech, Catalog No. 300-19)(“CM/SCF/flt-3 medium”). On about day 4 or 5, the density of the culturewas checked by performing a cell count and the culture was diluted to adensity of 275,000 cells/mL with fresh CM/SCF/flt-3 medium. On about day7, the culture was transferred to a sterile tube and a cell count wasperformed. The cells were spun at 1200 rpm and resuspended to a densityof 275,000 cells/mL with fresh CM/SCF/flt-3 medium.

This cycle was repeated, starting from day 0, a total of 3-5 times overthe expansion period.

When the culture is large and being maintained in multiple flasks and isto be resuspended, the contents of all of the flasks are combined into asingle container prior to performing a cell count. This ensures that anaccurate cell count is achieved and provides for a degree of uniformityof treatment for the entire population. Each flask is checked separatelyfor contamination under the microscope prior to combining to preventcontamination of the entire population.

Between days 17-24, the culture can begin to go into decline (i.e.,approximately 5-10% of the total number of cells die) and fail to expandas rapidly as before. The cells are then monitored on a daily basisduring this time, as complete failure of the culture can take place inas little as 24 hours. Once the decline has begun, the cells arecounted, spun down at 850 rpm for 15 minutes, and resuspended at adensity of 350,000 cells/mL in CM/SCF/flt-3 medium to induce one or twomore divisions out of the culture. The cells are monitored daily toavoid failure of the culture.

When greater than 15% cell death is evident in the progenitor cellculture and some debris is present in the culture, the CD34-negativeprogenitor cells are ready to be differentiated.

7.5.1.3 Differentiation of CD34-Negative Progenitor Cells into MucosalMast Cells

A second phase is performed to convert the expanded CD34-negativeprogenitor cells into differentiated mucosal mast cells. These mucosalcultured human mast cells (“CHMC”) are derived from CD34+cells isolatedfrom umbilical cord blood and treated to form a proliferated populationof CD34-negative progenitor cells, as described above. To produce theCD43-negative progenitor cells, the resuspension cycle for the culturewas the same as that described above, except that the culture was seededat a density of 425,000 cells/mL and 15% additional media was added onabout day four or five without performing a cell count. Also, thecytokine composition of the medium was modified such that it containedSCF (200 ng/mL) and recombinant human IL-6 (200 ng/mL; Peprotech,Catalog No. 200-06 reconstituted to 100 ug/mL in sterile 10 mM aceticacid) (“CM/SCF/IL-6 medium”).

Phases I and II together span approximately 5 weeks. Some death anddebris in the culture is evident during weeks 1-3 and there is a periodduring weeks 2-5 during which a small percentage of the culture is nolonger in suspension, but is instead attached to the surface of theculture vessel.

As during Phase I, when the culture is to be resuspended on day seven ofeach cycle, the contents of all flasks are combined into a singlecontainer prior to performing a cell count to ensure uniformity of theentire population. Each flask is checked separately for contaminationunder the microscope prior to combining to prevent contamination of theentire population.

When the flasks are combined, approximately 75% of the volume istransferred to the communal container, leaving behind about 10 mL or soin the flask. The flask containing the remaining volume was rappedsharply and laterally to dislodge the attached cells. The rapping wasrepeated at a right angle to the first rap to completely dislodge thecells.

The flask was leaned at a 45 degree angle for a couple of minutes beforethe remaining volume was transferred to the counting vessel. The cellswere spun at 950 rpm for 15 min prior to seeding at 35-50 mL per flask(at a density of 425,000 cells/mL).

7.5.1.4 Differentiation of CD34-Negative Progenitor Cells intoConnective Tissue-Type Mast Cells

A proliferated population of CD34-negative progenitor cells is preparedas above and treated to form a tryptase/chymase positive (connectivetissue) phenotype. The methods are performed as described above formucosal mast cells, but with the substitution of IL-4 for IL-6 in theculture medium. The cells obtained are typical of connective tissue mastcells.

7.5.1.5 Differentiation of CD34-Negative Progenitor Cells into BasophilCells

A proliferated population of CD34-negative progenitor cells is preparedas described in Section 6.4.1.2, above, and used to form a proliferatedpopulation of basophil cells. The CD34-negative cells are treated asdescribed for mucosal mast cells, but with the substitution of IL-3 (at20-50 ng/mL) for IL-6 in the culture medium.

7.5.2 CHMC Low Cell Density IgE Activation: Tryptase and LTC4 Assays

To duplicate 96-well U-bottom plates (Costar 3799) add 65 ul of compounddilutions or control samples that have been prepared in MT [137 mM NaCl,2.7 mM KCl, 1.8 mM CaCl₂, 1.0 mM MgCl₂, 5.6 mM Glucose, 20 mM Hepes (pH7.4), 0.1% Bovine Serum Albumin, (Sigma A4503)] containing 2% MeOH and1% DMSO. Pellet CHMC cells (980 rpm, 10 min) and resuspend in pre-warmedMT. Add 65 ul of cells to each 96-well plate. Depending on thedegranulation activity for each particular CHMC donor, load 1000-1500cells/well. Mix four times followed by a 1 hr incubation at 37° C.During the 1 hr incubation, prepare 6× anti-IgE solution [rabbitanti-human IgE (1 mg/ml, Bethyl Laboratories A80-109A) diluted 1:167 inMT buffer]. Stimulate cells by adding 25 ul of 6× anti-IgE solution tothe appropriate plates. Add 25 ul MT to un-stimulated control wells. Mixtwice following addition of the anti-IgE. Incubate at 37° C. for 30minutes. During the 30 minute incubation, dilute the 20 mM tryptasesubstrate stock solution [(Z-Ala-Lys-Arg-AMC2TFA; Enzyme SystemsProducts, #AMC-246)] 1:2000 in tryptase assay buffer [0.1 M Hepes (pH7.5), 10% w/v Glycerol, 10 uM Heparin (Sigma H-4898) 0.01% NaN₃]. Spinplates at 1000 rpm for 10 min to pellet cells. Transfer 25 ul ofsupernatant to a 96-well black bottom plate and add 100 ul of freshlydiluted tryptase substrate solution to each well. Incubate plates atroom temperature for 30 min. Read the optical density of the plates at355 nm/460 nm on a spectrophotometric plate reader.

Leukotriene C4 (LTC4) is also quantified using an ELISA kit onappropriately diluted supernatant samples (determined empirically foreach donor cell population so that the sample measurement falls withinthe standard curve) following the supplier's instructions.

7.5.3 CHMC High Cell Density IgE Activation: Degranulation (Tryptase,Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha, IL-13) Assays

Cultured human mast cells (CHMC) are sensitized for 5 days with IL-4 (20ng/ml), SCF (200 ng/ml), IL-6 (200 ng/ml), and Human IgE (CP 1035K fromCortx Biochem, 100-500 ng/ml depending on generation) in CM medium.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-2×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×anti-IgE. Mix wells with the cells and allow plates to incubate at 37°C. (5% CO₂) for one hour. After 1 hour incubation, pellet cells (10minutes, 1000 RPM) and collect 200 ul per well of the supernatant, beingcareful not to disturb pellet. Place the supernatant plate on ice.During the 7-hour step (see next) perform tryptase assay on supernatantthat had been diluted 1:500. Resuspend cell pellet in 240 ul of CM mediacontaining 0.5% DMSO and corresponding concentration of compound.Incubate CHMC cells for 7 hours at 37° C. (5% CO₂). After incubation,pellet cells (1000 RPM, 10 minutes) and collect 225 ul per well andplace in −80° C. until ready to perform ELISAS. ELISAS are performed onappropriately diluted samples (determined empirically for each donorcell population so that the sample measurement falls within the standardcurve) following the supplier's instructions.

7.5.4 BMMC High Cell Density IgE Activation: Degranulation(Hexosiminidase, Histamine), Leukotriene (LTC4), and Cytokine (TNFalpha,IL-6) Assays 7.5.4.1 Preparation of WEHI-Conditioned Medium

WEHI-conditioned medium was obtained by growing murine myelomonocyticWEHI-3B cells (American Type Culture Collection, Rockville, Md.) inIscove's Modified Eagles Media (Mediatech, Hemandon, Va.) supplementedwith 10% heat-inactivated fetal bovine serum (FBS; JRH Biosciences,Kansas City, Mo.), 50 μM 2-mercaptoethanol (Sigma, St. Louis, Mo.) and100 IU/mL penicillin-steptomycin (Mediatech) in a humidified 37° C., 5%CO₂/95% air incubator. An initial cell suspension was seeded at 200,000cells/mL and then split 1:4 every 3-4 days over a period of two weeks.Cell-free supernatants were harvested, aliquoted and stored at −80° C.until needed.

7.5.4.2 Preparation of BMMC Medium

BMMC media consists of 20% WEHI-conditioned media, 10% heat-inactivatedFBS (JHR Biosciences), 25 mM HEPES, pH7.4 (Sigma), 2 mM L-glutamine(Mediatech), 0.1 mM non-essential amino acids (Mediatech), 1 mM sodiumpyruvate (Mediatech), 50 μM 2-mercaptoethanol (Sigma) and 100 IU/mLpenicillin-streptomycin (Mediatech) in RPMI 1640 media (Mediatech). Toprepare the BMMC Media, all components are added to a sterile IL filterunit and filtered through a 0.2 μm filter prior to use.

7.5.4.3 Protocol

Bone marrow derived mast cells (BMMC) are sensitized overnight withmurine SCF (20 ng/ml) and monoclonal anti-DNP (10 ng/ml, Clone SPE-7,Sigma # D-8406) in BMMC media at a cell density of 666×10³ cells/ml.After sensitizing, cells are counted, pelleted (1000 rpm, 5-10 minutes),and resuspended at 1-3×10⁶ cells/ml in MT buffer. Add 100 ul of cellsuspension to each well and 100 ul of compound dilutions. The finalvehicle concentration is 0.5% DMSO. Incubate at 37° C. (5% CO₂) for 1hour. After 1 hour of compound treatment, stimulate cells with 6×stimulus (60 ng/ml DNP-BSA). Mix wells with the cells and allow platesto incubate at 37° C. (5% CO₂) for one hour. After 1 hour incubation,pellet cells (10 minutes, 1000 RPM) and collect 200 ul per well of thesupernatant, being careful not to disturb pellet, and transfer to aclean tube or 96-well plate. Place the supernatant plate on ice. Duringthe 4-5 hour step (see next) perform the hexosiminidase assay. Resuspendcell pellet in 240 ul WEI-conditioned media containing 0.5% DMSO andcorresponding concentration of compound. Incubate BMMC cells for 4-5hours at 37° C. (5% CO₂). After incubation, pellet cells (1000 RPM, 10minutes) and collect 225 ul per well and place in −80° C. until ready toperform ELISAS. ELISAS are performed on appropriately diluted samples(determined empirically for each donor cell population so that thesample measurement falls within the standard curve) following thesupplier's instructions.

Hexosaminidase assay: In a solid black 96-well assay plate, add 50 uLhexosaminidase substrate(4-methylumbelliferyl-N-acetyl-β-D-glucosaminide; 2 mM) to each well.Add 50 uL of BMMC cell supernatant (see above) to the hexoseaminidasesubstrate, place at 37° C. for 30 minutes and read the plate at 5, 10,15, and 30 minutes on a spectrophotometer.

7.5.5 Basophil IgE or Dustmite Activation: Histamine Release Assay

The basophil activation assay was carried out using whole humanperipheral blood from donors allergic to dust mites with the majority ofthe red blood cells removed by dextran sedimentation. Human peripheralblood was mixed 1:1 with 3% dextran T500 and RBCs were allowed to settlefor 20-25 min. The upper fraction was diluted with 3 volumes of D-PBSand cells were spun down for 10 min at 1500 rpm, RT. Supernatant wasaspirated and cells were washed in an equal volume MT-buffer. Finally,cells were resuspended in MT-buffer containing 0.5% DMSO in the originalblood volume. 80 uL cells were mixed with 20 uL compound in the presenceof 0.5% DMSO, in triplicate, in a V-bottom 96-well tissue culture plate.A dose range of 8 compound concentrations was tested resulting in a10-point dose response curve including maximum (stimulated) and minimum(unstimulated) response. Cells were incubated with compound for 1 hourat 37° C., 5% CO₂ after which 20 uL of 6× stimulus [1 ug/mL anti-IgE(Bethyl Laboratories) 667 au/mL house dustmite (Antigen Laboratories)]was added. The cells were stimulated for 30 minutes at 37° C., 5% CO₂.The plate was spun for 10 min at 1500 rpm at room temperature and 80 uLthe supernatant was harvested for histamine content analysis using thehistamine ELISA kit supplied by Immunotech. The ELISA was performedaccording to supplier's instructions.

7.5.6 Results

The results of low density CHMC assays (Section 6.4.3), the high densityBMMC assays (Section 6.4.5) and the basophil assays (Section 6.4.6) areprovided in TABLE 1. The results of the high density CHMC assays(Section 6.4.4) are provided in TABLE 2. In TABLES 1 and 2, all reportedvalues are IC₅₀s (in μM). A value of “9999” indicates an IC₅₀>10 μM,with no measurable activity at a 10 μM concentration. Most compoundstested had IC₅₀s of less than 10 μM, with many exhibiting IC₅₀s in thesub-micromolar range.

7.6 The 2,4-Pyrimidinediamine Compounds Inhibit FcγRI Receptor-MediatedDegranulation

The ability of the 2,4-pyrimidinediamine compounds of the invention toinhibit FcγRI-mediated degranulation was demonstrated with CompoundsR921218, R921302, R921303, R940347, R920410, R927050, R940350, R935372,R920323, R926971 and R940352 in assays similar to those described inSection 6.4, with the exception that the cells were not primed with IgEand were activated with rabbit anti-human IgG Fab fragment (BethylLaboratories, Catalog No. A80-105).

All of the compounds tested exhibited IC₅₀s in the sub micromolar range.

TABLE 1 Low Density CHMC CHMC CHMC CHMC CHMC Basophils Basophils Testanti-IgE Ionomycin anti-IgE anti-IgE Ionomycin anti-IgE IonomycinCompound Tryptase Tryptase LTC4 Hexos. Hexos. Histamine HistamineR008951 R008952 R008953 R008955 R008956 R008958 R067934 R067963 R070153R070790 1.665 9999 R070791 R081166 R088814 R088815 R091880 R092788R908696 3.553 R908697 9999 9999 R909236 0.996 9999 R909237 9999 9999R909238 0.174 9999 R909239 0.264 9999 R909240 0.262 9999 R909241 0.1819999 R909242 0.567 9999 R909243 0.263 >10 R909245 0.255 6.242 R9092460.169 9999 R909247 2.393 9999 R909248 3.582 9999 R909249 9999 9999R909250 8.025 9999 R909251 0.138 9999 R909252 0.248 9999 R909253 7.9559999 R909254 0.136 9999 R920664 9999 9999 R920665 1.1 9999 R920666 2.539999 R920668 3.2 9999 R920669 0.42 9999 R920670 2.18 9999 R920671 99999999 R920672 9999 9999 R920818 9999 9999 R920819 10 9999 R920820 99999999 R920846 9999 9999 R920860 1.009 9999 R920861 0.598 >10 R9208931.239 9999 R920894 0.888 5.566 R920910 0.751 7.922 R920917 1.579 9.729R921218 0.499 9999 0.55 0.6 9999 0.24 9999 R921219 0.059 9999 0.025 9999R925734 9.2 >10 R925747 1.021 3.1 R925755 0.898 9999 R925757 2.8 9999R925758 1.175 9999 R925760 4.85 9999 R925765 6.8 9999 R925766 8.9 9999R925767 10 R925768 9999 R925769 9999 R925770 9999 R925771 0.5 2.8 0.22R925772 9999 9999 R925773 0.673 9999 R925774 0.435 9999 R925775 0.2259999 0.2 R925776 2.1 9999 R925778 0.225 9999 0.18 R925779 0.265 99990.19 R925783 2.9 9999 R925784 3.2 9999 R925785 2.5 9999 R925786 1.859999 R925787 9 9999 R925788 2.4 9999 R925790 9999 9999 R925791 9999 9999R925792 6.25 9999 R925794 9999 9999 R925795 9999 9999 R925796 2 9999R925797 0.85 9999 0.28 R925798 9999 9999 R925799 9999 9999 R925800 99999999 R925801 9999 9999 R925802 9999 9999 R925803 9999 9999 R925804 99999999 R925805 9999 9999 R925806 9999 9999 R925807 9999 9999 R925808 99999999 R925810 9999 9999 R925811 3.3 9999 R925812 5.8 9999 R925813 99999999 R925814 9999 9999 R925815 9999 9999 R925816 6 9999 R925819 99999999 R925820 9999 9999 R925821 9999 9999 R925822 9999 9999 R925823 99999999 R925824 9999 9999 R925837 9999 9999 R925838 9999 9999 R925839 99999999 R925840 9999 9999 R925841 9999 9999 R925842 7.3 9999 R925843 99999999 R925844 5.1 9999 R925845 2.3 9999 R925846 9999 9999 R925849 8.29999 R925851 0.925 9999 R925852 3 9999 R925853 9999 9999 R925854 99999999 R925855 4.2 9999 R925856 9.85 9999 R925857 5.95 9999 R925858 8.057.3 R925859 9999 9999 R925860 9999 9999 R925861 9999 9999 R925862 0.79999 R925863 0.274 9999 R925864 9999 9999 R925865 9999 9999 R926016 99999999 R926017 1.43 9999 0.53 9999 R926018 9999 10 R926037 9999 9999R926038 9999 9999 R926039 9999 9999 R926058 9999 9999 R926064 6.2R926065 3.5 R926068 >10 R926069 9.1 R926072 >10 R926086 2.5 9999 R9261080.76 0.787 6.4 0.95 9999 R926109 0.538 5.5 0.73 0.55 >10 0.15 9999R926110 1.071 9999 1.42 1.2 >10 0.3 9999 R926113 0.413 0.49 0.413 99990.27 9999 R926114 3.427 8.1 1.7 10 R926145 4.764 >10 R926146 1.59 0.7616.7 R926147 1.899 >10 R926206 >10 >10 R926209 >10 9999 R926210 0.9269999 0.8 700 9999 0.37 >10 R926211 1.299 9.8 2.7 9999 1.55 >10 R9262120.654 9999 0.45 0.5 >10 R926213 1.639 5.5 1.75 >10 R926218 >10 R9262191.102 6.7 R926220 >10 R926221 8.5 R926222 >10 R926223 >10 R926224 >10R926225 >10 R926228 >10 R926229 >10 R926230 >10 R926234 >10 R9262371.207 6.2 R926240 0.381 1.7 0.145 R926241 7 9999 R926242 4.2 9999R926243 3.1 9999 R926245 3.1 9.4 R926248 0.9 9999 0.76 R926249 0.5 99990.25 R926252 2.8 R926253 0.8 0.675 R926254 1.3 4 R926255 1.4 4.5 R9262560.275 5.1 0.23 R926257 1.5 7.5 R926258 0.9 9999 0.59 R926259 2.5 6.2R926319 9999 9999 R926320 9999 9999 R926321 9999 9999 R926325 9999 9999R926331 9999 9999 R926339 0.66 9999 R926340 3.23 9999 R926341 0.875 9999R926342 10 9999 R926376 9999 R926386 9999 9999 R926387 0.65 9999 0.7R926394 9999 9999 R926395 0.875 6.4 0.29 R926396 0.7 2.6 0.16 R9263979999 9999 R926398 9999 9999 R926399 9999 9999 R926400 9999 9999 R9264019999 9999 R926402 9999 9999 R926403 9999 9999 R926404 9999 9999 R9264053.4 9999 R926406 9999 9999 R926408 9.6 9999 R926409 3.15 9999 R9264110.69 2.5 R926412 0.62 9999 R926461 0.725 9999 R926467 1.175 8.8 R9264699999 R926474 2.5 9999 R926475 2.15 >10 R926476 0.6 7.7 R926477 0.27 9999R926478 9999 R926479 9999 R926480 1.9 9999 R926481 1.445 9999 R9264821.037 >10 R926483 9999 R926484 1.523 9999 R926485 4.012 9999 R9264860.647 7.403 R926487 0.554 8.867 1.25 R926488 0.331 >10 0.752 R9264891.414 >10 R926490 1.571 9999 R926491 1.158 >10 R926492 0.645 9999R926493 0.25 9.181 0.078 R926494 0.313 9999 0.078 R926495 0.121 >100.078 0.04 9999 R926496 0.571 >10 R926497 0.138 9999 0.27 9999 R9264980.209 >10 R926499 0.29 >10 R926500 0.418 >10 R926501 0.298 >10 0.6099999 R926502 0.483 >10 0.405 9999 R926503 0.452 >10 R926504 0.569 >10R926505 0.145 9999 R926506 0.343 9999 R926508 0.127 9999 0.065 9999R926509 1.16 9999 R926510 0.44 >10 R926511 0.786 >10 R926514 9999 9999R926516 1 9999 R926526 9999 9999 R926527 9999 9999 R926528 8.75 9999R926535 9999 9999 R926536 9999 9999 R926555 9999 9999 R926559 7.7 9999R926560 9999 9999 R926562 9999 9999 R926563 9999 9999 R926564 3.75 9999R926565 0.625 3.3 R926566 2.73 9999 R926567 9.3 9999 R926569 0.61 3.07R926571 9999 9999 R926572 1.8 6.08 R926574 1.96 2.63 R926576 9999 9999R926579 9999 9999 R926580 10 9999 R926582 1.3 9999 R926583 9999 9999R926584 9999 9999 R926585 9999 9999 R926586 2.75 9999 R926587 9999 9999R926588 7.85 9999 R926589 0.325 10 R926591 2.62 9999 R926593 0.68 8.30.495 R926594 9999 9999 R926595 4.85 9999 R926604 2.85 9999 R926605 2.459999 R926614 0.228 9999 R926615 0.445 9999 R926616 0.625 3.25 R9266179.45 9999 R926620 8.35 9999 R926623 9999 9999 R926662 9999 9999 R9266639999 9999 R926675 0.63 9999 R926676 0.76 9999 R926680 1.71 9999 R9266810.775 9999 R926682 8.41 9999 R926683 10 9999 R926688 2.25 >10 R9266900.146 >10 R926696 0.309 >10 R926698 9999 R926699 0.76 9999 R9267000.157 >10 R926701 2.2 9999 R926702 0.886 9999 R926703 0.525 9999 R9267040.564 9999 R926705 0.263 9999 0.533 R926706 0.07 2.406 0.078 R9267070.214 9999 R926708 0.472 9999 R926709 0.858 9999 R926710 1.763 9999R926711 1.245 9999 R926712 1.084 9999 R926713 0.446 8.741 R9267140.428 >10 R926715 0.588 >10 R926716 1.06 9999 R926717 7.874 9999 R9267181.826 9999 R926719 0.1335 4.024 R926720 1.555 9999 R926721 4.441 9999R926722 5.96 9999 R926723 2.591 9999 R926724 2.059 9999 R926725 0.4319999 R926726 9999 9999 R926727 0.387 9999 R926728 0.482 >10 R9267300.251 9999 R926731 9999 9999 R926732 0.444 9999 R926733 1.496 9999R926734 4.493 9999 R926735 3.712 9999 R926736 0.288 9999 R926737 0.0599999 R926738 0.342 9999 R926739 0.508 9999 R926740 4.422 9999 R9267412.908 9999 R926742 0.127 0.043 9999 R926743 9999 R926744 9999 R9267450.083 9999 R926746 0.989 9999 R926747 0.213 >10 R926748 0.345 >10R926749 0.472 9999 R926750 0.361 >10 R926751 0.598 9999 R926764 0.2525.64 R926765 0.324 4.39 R926766 0.756 9999 R926767 0.387 >10 R9267680.443 >10 R926769 1.067 9999 R926770 0.583 9999 R926771 2.049 9999R926772 0.337 7.501 R926773 0.548 7.849 R926774 1.934 7.935 R9267753.47 >10 R926776 0.81 9999 R926777 0.378 9999 R926778 0.414 9999 R9267799999 9999 R926780 0.152 >10 R926781 0.573 9999 R926782 0.173 >10 R9267830.304 >10 R926784 0.252 9999 R926785 0.222 >10 R926786 0.504 9999R926787 5.422 9999 R926788 0.336 6.341 R926789 2.315 9999 R926790 0.4627.412 R926791 0.233 >10 R926792 3.197 9999 R926793 3.073 9999 R9267952.041 >10 R926796 0.914 9999 R926797 2.235 9999 R926798 2.347 5.87R926799 9999 9999 R926800 4.581 9999 R926801 10 9999 R926802 1.251 >10R926803 1.541 >10 R926804 1.578 7.109 R926805 0.764 9999 R926806 0.3749999 R926807 0.291 9999 R926808 0.368 9999 R926809 0.78 3.052 R9268101.221 9999 R926811 3.662 9999 R926812 0.185 >10 R926813 0.152 9999R926814 1.101 9999 R926815 1.181 9999 R926816 0.084 9999 R935000 99999999 R935001 9999 9999 R935002 9999 9999 R935003 9999 9999 R935004 99999999 R935005 9999 9999 R935006 10 9.8 R935016 9999 9999 R935019 8.8 9999R935020 9999 9999 R935021 9999 9999 R935023 9999 9999 R935025 1.04 9999R935029 2.83 9999 R935075 0.93 9999 R935076 4.15 9999 R935077 9999 9999R935114 1.725 9999 R935117 9999 R935134 0.909 1.799 R935135 10 9999R935136 0.952 2.129 R935137 10 9999 R935138 0.096 0.552 R935139 0.8469999 R935140 0.275 0.959 R935141 0.727 >10 R935142 0.873 >10 R9351430.573 >10 R935144 0.63 9999 R935145 0.548 >10 R935146 3.802 9999 R9351471.404 9999 R935148 2.218 9.423 R935149 0.708 >10 R935150 1.926 9.738R935151 0.479 >10 R935152 0.505 9.316 R935153 0.238 >10 R9351540.127 >10 R935155 0.401 9999 R935156 0.149 >10 R935157 0.256 4.656R935158 0.551 >10 R935159 0.232 4.135 R935160 0.202 >10 R935161 0.2779999 R935162 0.269 >10 R935163 9999 9999 R935164 0.204 9999 R9351654.988 9999 R935166 0.568 9999 R935167 2.132 >10 R935168 0.488 9.484R935169 0.999 8.007 R935170 0.673 9999 R935171 0.536 9999 R935172 1.3856.808 R935173 0.454 >10 R935174 1.384 9999 R935175 0.885 9999 R9351761.169 9999 R935177 0.889 >10 R935178 0.515 9999 R935179 0.557 9999R935180 1.22 9999 R935181 1.76 9999 R935182 0.124 2.469 R935183 0.7299999 R935184 0.605 9999 R935185 0.351 6.642 R935186 0.211 9999 R9351879.059 >10 R935188 0.239 9999 R935189 0.619 9999 R935190 0.156 9999R935191 0.151 9999 R935192 0.337 9999 R935193 0.136 9999 R935194 0.119999 R935196 0.117 9999 R935197 0.174 >10 R935198 0.126 >10 R9351990.45 >10 R935202 0.181 9.765 R935203 0.562 >10 R935204 0.554 9999R935205 2.959 9999 R935206 4.711 9999 R935207 9999 9999 R935208 1.2749999 R935209 0.526 1.035 R935211 1.238 9999 R935212 1.427 9999 R9352130.619 10 R935214 0.453 5.499 R935218 4.712 9999 R935219 5.409 9999R935220 3.789 9999 R940089 9999 9999 R940090 9999 9999 R940095 9999 9999R940100 9999 9999 R940215 0.845 9999 R940216 0.2675 7.3 R940217 99999999 R940222 9999 9999 R940233 0.132 >10 R940235 0.8 >10 R940250 R940251R940253 1.006 >10 R940254 0.986 9999 R940255 1.033 9999 R940256 1.1049999 R940257 0.667 9999 R940258 0.473 5.72 R940260 1.126 9999 R9402619999 9999 R940262 9999 9999 R940263 9999 9999 R940264 10 9999 R9402650.239 >10 R940266 9999 9999 R940267 3.151 9999 R940269 1.654 9999R940270 2.144 8.739 R940271 0.401 6.821 R940275 0.862 9999 R940276 0.2119999 R940277 0.141 9999 R940280 6.999 9999 R940281 0.525 5.529 R9402820.401 3.015 R940283 0.553 4.982 R940284 0.465 3.744 R940285 3.499 9999R940286 0.337 7.082 R940287 0.288 7.684 R940288 0.208 9999 R940289 0.2729999 R940290 0.116 9999 R940291 0.396 9999 R940292 0.683 9999 R9402939999 9999 R940294 1.366 9999 R940295 0.126 8.812 R940296 0.41 >10R940297 3.465 10 R945025 9999 9999 R945032 0.37 9999 R945033 9999 9999R945034 1.85 9999 R945035 9999 9999 R945036 9999 9999 R945037 9999 9999R945038 9999 9999 R945040 9999 9999 R945041 9999 9999 R945042 9999 9999R945043 9999 9999 R945045 9999 9999 R945046 0.82 >10 R945047 0.845 9999R945048 0.76 9999 R945051 0.95 >10 R945052 0.425 2.48 R945053 0.11851.48 R945056 10 9999 R945057 10 9999 R945060 0.9375 >10 R945061 10 9999R945062 0.625 >10 R945063 1.55 >10 R945064 0.53 >10 R945065 1.425 >10R945066 5.2 nd R945067 9999 nd R945068 9999 nd R945070 0.45 >10 R9450710.205 >10 R945096 1.75 >10 R945097 10 9999 R945109 1.025 >10 R9451100.602 9999 R945117 4.077 9999 R945118 0.668 9999 R945124 0.69 7.852R945125 0.896 >10 R945126 9999 9999 R945127 0.704 8.955 R945128 0.6858.8 R945129 1.003 >10 R945130 1.874 9999 R945131 0.77 9999 R945132 0.5718.77 R945133 1.064 >10 R945134 9999 9999 R945135 0.986 8.245 R9451371.649 >10 R945138 1.058 6.733 R945139 1.016 >10 R945140 0.573 >10R945142 1.049 >10 R945144 0.244 9999 R945145 9999 >10 R945146 3.756 9999R945147 3.546 9999 R945148 0.307 9999 R945149 0.391 >10 R9451500.467 >10 R945151 4.07 9999 R945152 6.94 9999 R945153 0.688 6.561R945155 1.878 >10 R945156 0.787 9999 R945157 1.477 9999 R945162 99999999 R945163 0.922 4.251 R945164 10 9999 R945165 9999 9999 R945166 99999999 R945167 0.761 9999 R945168 10 9999 R945169 10 9999 R9451700.661 >10 R945171 1.327 9999 R945172 1.179 9999 R945173 1.419 9999R945175 1.648 9999 R950082 9999 9999 R950083 9999 9999 R950090 9999 9999R921302 0.37 9999 0.19 9999 R950092 9999 9999 R950093 0.64 5.55 R9501000.71 >10 R950107 0.46 >10 R950108 2.075 >10 R950109 7.95 R950120 3 9999R950121 4.25 >10 R950122 3.025 9999 R950123 3.25 8.45 R950125 1.375 6.3R950129 0.665 >10 R950130 4.9 R950131 9999 R950132 9 R950133 2.2 >10R950134 1.875 9999 R950135 0.85 >10 R950137 2.23 9999 R950138 9.5R950139 1.375 9999 R950140 2.825 9999 R950141 0.31 >10 R950142 10R950143 8.23 R950144 10 R950145 9999 R950146 9999 R950147 9999 R9501482.275 9999 R950149 10 9999 R950150 9999 9999 R950151 9999 R950152 10R950153 9999 R950154 2.075 9999 R950155 9999 R950156 9999 R950157 9999R950158 9.98 R950159 0.61 9999 R950160 1 9999 R950162 0.434 >10 R9501630.874 9999 R950164 1.893 9999 R950165 1.288 9999 R950166 1.889 9999R950167 9999 9999 R950168 6.496 8.653 R950169 1.273 9.518 R950170 99999999 R950171 0.585 >10 R950172 0.983 9999 R950173 2.368 >10 R9501744.618 9999 R950175 1.688 9999 R950176 1.342 9999 R950177 2.361 8.434R950178 0.688 >10 R950179 0.955 >10 R950180 0.278 9999 R950181 0.2549999 R950182 0.627 9999 R950183 4.797 9999 R950184 2.222 9999 R9501851.03 8.81 R950186 0.558 >10 R950187 0.724 >10 R950188 2.327 9999 R95018910 9999 R950190 1.573 9999 R950191 0.178 9999 R950192 0.244 9999 R9501930.61 9999 R950194 2.04 9999 R950195 0.473 9999 R950196 2.2 9999 R9501970.531 9999 R950198 0.406 >10 R950199 0.408 9999 R950200 0.245 9999R950201 0.261 9999 R950202 3.218 9999 R950203 9.035 9999 R950204 6.2859999 R950205 8.997 9999 R950206 3.66 >10 R950207 0.164 9999 R9502080.267 9999 R950209 0.748 9999 R950210 10 9999 R950211 10 9999 R9502120.253 9999 R950213 9999 9999 R950214 10 9999 R950215 0.409 9999 R9502160.327 9999 R950217 0.34 9999 R950218 0.292 9999 R950219 0.439 9999R950220 0.489 9999 R950221 0.636 9999 R950222 0.865 9999 R950223 0.7639999 R950224 0.687 9999 R950225 5.283 9999 R950226 1.374 9999 R9502271.029 9999 R950229 0.98 9999 R950230 7.91 9999 R950231 1.968 9999R950232 10 9999 R950233 0.98 9999 R950234 10 9999 R950235 4.095 9999R950236 0.955 9999 R950237 9999 9999 R950238 10 9999 R950239 2.063 9999R950240 1.766 9999 R950241 3.275 9999 R950251 9999 9999 R950253 0.6979999 R950254 0.496 9999 R950255 10 9999 R908698 1.67 9999 R908699 0.2179999 R908700 1.273 9999 R908701 0.099 7.643 R908702 0.104 7.395 R9087030.63 9999 R908704 0.511 9999 R908705 0.801 9999 R908706 0.445 9999R908707 1.834 9999 R908709 2.414 R908710 1.838 99 R908711 1.761 R9087120.075 99 R908734 1.379 R909255 0.244 9999 R909259 0.43 9999 R9092601.041 9999 R909261 0.93 9999 R909263 0.289 9999 R909264 R909265 99R909266 99 R909267 0.589 9999 R909268 0.071 9999 R909290 0.226 R9092921.172 R909308 0.671 9999 R909309 0.083 9999 R920394 R920395 0.092 9999R920396 R920397 R920398 R920399 R920404 R920405 R920406 R920407 R920408R920410 0.125 9999 R920411 0.564 9999 R925745 1.766 9999 R926238 9999R926752 0.338 9999 R926753 0.108 9999 R926754 0.388 9999 R926755 1.6939999 R926756 1.365 9999 R926757 0.158 9999 R926759 0.688 9999 R9267602.893 9999 R926761 0.245 9999 R926762 0.386 9999 R926763 0.195 9999R926794 1.382 9999 R926826 0.613 9999 R926827 1.098 9999 R926828 0.3069999 R926829 0.688 9999 R926830 0.569 10 R926831 0.133 10 R926832 0.3659999 R926833 1.129 9999 R926834 0.145 9999 R926835 0.296 9999 R926836 109999 R926837 2.994 9999 R926838 0.583 9999 R926839 0.161 9999 R9268401.1 9999 R926841 0.551 9999 R926842 7.733 9999 R926843 7.371 9999R926844 1.1 9999 R926845 2.558 7.812 R926846 0.86 6.264 R926847 1.4796.264 R926848 0.254 10 R926851 0.446 R926855 9999 9999 R926856 0.7349999 R926857 1.209 9999 R926859 R926860 1.949 99 R926862 0.774 9999R926863 R926866 R926870 3.294 R926871 2.146 R926874 0.638 9999 R9268790.397 9999 R926880 R926881 R926883 R926885 R926886 R926887 1.747 R9268900.361 9999 R926891 0.152 9999 R926892 0.685 9999 R926893 10 9999 R9268949999 9999 R926895 0.339 9999 R926896 1.622 9999 R926897 1.727 9999R926898 1.1 9999 R926899 1.1 9999 R926900 9999 9999 R926902 1.37 4.586R926903 0.243 9999 R926904 0.538 R926905 99 R926906 0.794 R926907 0.764R926908 0.585 R926909 0.379 R926913 0.548 9999 R926914 1.86 9999 R9269151.713 9999 R926916 1.958 9999 R926917 1.169 9999 R926918 2.521 9999R926919 1.413 9999 R926922 0.305 9999 R926923 0.346 9999 R926925 0.30799 R926926 0.401 9999 R926927 0.348 9999 R926928 0.575 9999 R9269291.916 9999 R926930 99 9999 R926931 R926932 0.31 9999 R926933 R926934R926935 4.44 R926936 R926937 R926938 R926939 3.615 R926940 7.754 R9269414.195 R926942 4.81 R926943 R926944 0.225 99 R926945 0.457 9999 R926946R926947 0.354 9999 R926948 0.246 9999 R926949 0.089 9999 R926950 99 9999R926951 0.183 9999 R926953 0.049 9999 R926954 0.284 9999 R926955 0.369999 R926956 0.211 9999 R927016 1.408 R927017 2.449 R927018 1.446R927019 1.179 R927020 1.316 9999 R927023 0.918 9999 R935221 9999 9999R935222 0.52 9999 R935223 0.469 9999 R935224 4.578 9999 R935225 6.4959999 R935237 0.24 9999 R935238 1.854 9999 R935239 0.609 9999 R9352400.606 9999 R935242 2.855 9999 R935248 1.1 9999 R935249 1.1 9999 R9352501.1 9999 R935251 R935252 R935253 R935255 0.374 9999 R935256 0.324 9999R935258 1.191 9999 R935259 1.777 9999 R935261 0.391 9999 R935262 0.5169999 R935263 0.106 10 R935264 0.135 9999 R935266 2.97 R935267 2.463R935268 1.059 R935269 1.715 R935271 R935276 2.33 R935277 22.883 8.9R935278 4.753 9999 R935279 0.889 9999 R935280 99 R935281 1.399 9999R935286 1.158 9999 R935287 0.403 9999 R935288 1.58 9999 R935289 1.6889999 R935290 0.34 9999 R935291 1.364 9999 R935292 0.483 9999 R9352930.141 9999 R935294 0.388 9999 R935295 1.943 9999 R935296 99 9999 R9352977.328 9999 R935298 0.252 99 R935299 0.21 9999 R935300 0.243 9999 R9353014.05 99 R935302 0.189 9999 R935303 0.244 99 R935304 0.188 9999 R9353050.495 9999 R935306 0.345 99 R935307 0.139 99 R935308 0.275 9999 R935309R935310 R935320 2.769 R935321 2.986 R935322 3.416 R935323 9999 R9353249999 R935336 0.341 9999 R935337 9999 R935338 0.411 9999 R935339 9999R935340 3.606 R935351 9999 9999 R935352 R935353 9999 9999 R935354 999999 R935355 9999 9999 R935356 99 R935357 99 9999 R935358 9999 9999R935359 1.027 9999 R935360 0.903 9999 R935361 1.438 9999 R935362 0.4099999 R935363 0.405 9999 R935364 0.563 9999 R935365 0.373 9999 R9353660.216 9999 R935367 0.053 9999 R940079 9999 R940110 9999 9999 R9402992.497 9999 R940300 10 9999 R940301 1.975 9999 R940304 9999 9999 R9403061.1 9999 R940307 0.291 9999 R940308 0.612 4.168 R940309 1.132 9999R940311 1.95 R940312 2.557 R940314 4.197 R940316 1.858 R940317 0.9139999 R940318 3.792 R940319 9999 R940321 9999 R940323 0.048 9999 R9403371.098 R940338 0.073 9999 R921303 0.033 99 R940345 1.712 R940346 0.142 99R940347 0.063 99 R940348 2.189 R940349 0.044 7.4 R940350 0.092 4 R9403510.12 2.7 R940352 0.101 9999 R940353 0.091 9999 R940354 0.115 99 R9452360.562 9999 R945237 0.461 9999 R945242 0.247 9999 R945263 1.642 R9213040.085 9999 R945299 R950244 9999 R950245 9999 R950246 9999 R950247 9999R950261 0.611 9999 R950262 0.285 9999 R950263 0.284 3.299 R950264 0.1989999 R950265 0.312 9999 R950266 0.645 9999 R950267 0.18 9999 R9502909999 9999 R950291 9999 9999 R950293 3.689 8.155 R950294 2.005 8.005R950295 2.041 8.795 R950296 0.495 9999 R950344 99 R950345 1.962 99R950346 0.345 9999 R950347 0.548 R950348 0.066 R950349 0.078 9999R950356 R950368 0.038 9999 R950371 R950372 1.348 9999 R950373 R9503740.599 9999 R950376 2.539 R950377 99 R950378 R950379 0.545 9999 R950380 39999 R950381 0.11 99 R950382 R950383 0.114 9999 R950385 R950386 0.973R950388 2.518 R950389 0.612 9999 R950391 999 9999 R950392 0.956 9999R950393 0.404 9999 R945028 R935241 R940298 R940302 R940303 R940305R935260 9999 R909258 R940313 9999 R940315 9999 R935275 9999 R940320 9999R940322 9999 9999 R926910 9999 9999 R926911 9999 9999 R926912 9999 9999R926853 9999 9999 R926852 9999 9999 R926854 9999 9999 R926920 9999 9999R926921 99 9999 R926924 99 9999 R926858 R926861 9999 9999 R945298 99999999 R940328 9999 R926869 R926873 9999 R926875 9999 R926876 9999 R9268779999 R940336 9999 R926878 9999 R926882 9999 R926884 9999 R926889 9999R920400 9999 R920401 9999 R920402 9999 R920403 9999 R940342 99 R9204099999 R940344 9999 R926888 9999 R926758 R927024 0.326 99 R927025 0.326R927026 9999 9999 R927027 9999 9999 R927028 0.208 9999 R927029 R9270300.26 9999 R927031 0.215 99 R927032 0.899 R927035 0.583 9999 R927036R927037 0.233 9999 R927038 1.05 9999 R927039 1.23 9999 R927040 1.05 9999R927041 0.788 9999 R927042 R935270 R935368 0.082 9999 R935369 0.255 9999R935370 R935371 0.794 9999 R935372 0.06 9999 R935373 0.274 9999 R9353740.356 9999 R935375 10 9999 R935376 R935377 R935378 0.566 9999 R935379R935380 1.61 99 High Density Basophils BMMC BMMC BMMC BMMC BMMC BMMCTest Dust mite anti-IgE Ionomycin anti-IgE anti-IgE anti-IgE anti-IgECompound Histamine hexos Hexos. histamine LTC4 TNF-alpha IL-6 R008951R008952 R008953 R008955 R008956 R008958 R067934 R067963 R070153 R070790R070791 R081166 R088814 R088815 R091880 R092788 R908696 R908697 R909236R909237 R909238 <0.22 <0.22 0.521 0.432 <0.22 R909239 R909240 R909241<0.22 <0.22 1.021 0.253 <0.22 R909242 R909243 R909245 R909246 R909247R909248 R909249 R909250 R909251 R909252 R909253 R909254 R920664 R920665R920666 R920668 R920669 R920670 R920671 R920672 R920818 R920819 R920820R920846 R920860 R920861 R920893 R920894 R920910 R920917 R921218 0.3020.133 9999 0.203 0.766 0.274 0.100 R921219 0.020 0.069 0.058 0.040 0.0390.009 R925734 9999 9999 R925747 3.1 R925755 R925757 R925758 R925760R925765 R925766 R925767 R925768 R925769 R925770 R925771 R925772 R925773R925774 R925775 R925776 R925778 R925779 R925783 R925784 R925785 R925786R925787 R925788 R925790 R925791 R925792 R925794 R925795 R925796 R925797R925798 R925799 R925800 R925801 R925802 R925803 R925804 R925805 R925806R925807 R925808 R925810 R925811 R925812 R925813 R925814 R925815 R925816R925819 R925820 R925821 R925822 R925823 R925824 R925837 R925838 R925839R925840 R925841 R925842 R925843 R925844 R925845 R925846 R925849 R925851R925852 R925853 R925854 R925855 R925856 R925857 R925858 R925859 R925860R925861 R925862 R925863 R925864 R925865 R926016 9999 9999 R926017 1.49.6 R926018 8.5 9999 R926037 9999 9999 R926038 9999 9999 R926039 99999999 R926058 9999 9999 R926064 5.9 7.3 R926065 9999 9999 R926068 7.4 8.2R926069 4.5 4.4 R926072 9999 9999 R926086 2.8 7.3 R926108 0.9 9999R926109 0.6 3.2 R926110 1 4.5 R926113 0.65 9999 R926114 9999 9999R926145 2.4 8.8 R926146 1.35 5 R926147 2 7.1 R926206 6.6 8.6 R926209 109.1 R926210 0.6 >10 R926211 3.9 >10 R926212 0.5 5 R926213 R926218 99999999 R926219 2.5 3.2 R926220 9999 9999 R926221 9.9 9999 R926222 99999999 R926223 9999 9999 R926224 9999 9999 R926225 9999 9999 R926228 9999R926229 R926230 R926234 9999 R926237 1.9 R926240 R926241 R926242 R926243R926245 R926248 R926249 R926252 R926253 R926254 R926255 R926256 R926257R926258 R926259 R926319 R926320 R926321 R926325 R926331 R926339 R926340R926341 R926342 R926376 R926386 R926387 R926394 R926395 R926396 R926397R926398 R926399 R926400 R926401 R926402 R926403 R926404 R926405 R926406R926408 R926409 R926411 R926412 R926461 R926467 R926469 R926474 R926475R926476 R926477 R926478 R926479 R926480 R926481 R926482 R926483 R926484R926485 R926486 R926487 R926488 R926489 R926490 R926491 R926492 R926493R926494 R926495 0.038 0.056 0.089 0.24 0.077 0.028 R926496 R926497 0.205R926498 <0.22 0.515 0.995 0.614 <0.22 R926499 R926500 R926501 0.645R926502 0.491 R926503 R926504 R926505 <0.22 <0.22 <0.22 <0.22 <0.22R926506 R926508 0.054 0.086 0.107 0.162 0.054 0.026 R926509 R926510R926511 R926514 R926516 R926526 R926527 R926528 R926535 R926536 R926555R926559 R926560 R926562 R926563 R926564 R926565 R926566 R926567 R926569R926571 R926572 R926574 R926576 R926579 R926580 R926582 R926583 R926584R926585 R926586 R926587 R926588 R926589 R926591 R926593 R926594 R926595R926604 R926605 R926614 R926615 R926616 R926617 R926620 R926623 R926662R926663 R926675 R926676 R926680 R926681 R926682 R926683 R926688 R926690R926696 R926698 R926699 R926700 R926701 R926702 R926703 R926704 R926705R926706 R926707 <0.056 <0.056 0.39 0.088 <0.056 R926708 R926709 R926710R926711 R926712 R926713 R926714 R926715 R926716 R926717 R926718 R926719R926720 R926721 R926722 R926723 R926724 R926725 R926726 R926727 R926728R926730 R926731 R926732 R926733 R926734 R926735 R926736 R926737 0.0750.073 0.046 0.068 0.017 R926738 R926739 R926740 R926741 0.961 1.025 99990.772 0.537 R926742 0.055 0.041 0.055 0.105 0.053 0.022 R926743 R926744R926745 R926746 R926747 R926748 R926749 R926750 R926751 R926764 R926765R926766 R926767 R926768 R926769 R926770 R926771 R926772 R926773 R926774R926775 R926776 R926777 R926778 R926779 R926780 <0.22 <0.22 0.461 <0.22<0.22 R926781 R926782 <0.22 <0.22 1.461 0.276 <0.22 R926783 R926784R926785 0.989 0.561 1.411 1.312 0.513 R926786 R926787 R926788 R926789R926790 R926791 0.064 <0.056 0.896 0.205 <0.056 R926792 R926793 R926795R926796 R926797 R926798 R926799 R926800 R926801 R926802 R926803 R926804R926805 R926806 R926807 R926808 R926809 R926810 R926811 R926812 R926813R926814 R926815 R926816 R935000 R935001 R935002 R935003 R935004 R935005R935006 R935016 R935019 R935020 R935021 R935023 R935025 R935029 R935075R935076 R935077 R935114 R935117 R935134 R935135 R935136 R935137 R935138<0.22 <0.22 0.373 0.409 <0.22 R935139 R935140 R935141 R935142 R935143R935144 R935145 R935146 R935147 R935148 R935149 R935150 R935151 R935152R935153 R935154 0.104 0.085 0.547 0.131 0.041 R935155 R935156 <0.22<0.22 0.433 0.22 <0.22 R935157 R935158 R935159 R935160 <0.22 0.317 0.8760.484 <0.22 R935161 R935162 R935163 R935164 R935165 R935166 R935167R935168 R935169 R935170 R935171 R935172 R935173 R935174 R935175 R935176R935177 R935178 R935179 R935180 R935181 R935182 R935183 R935184 R935185R935186 R935187 R935188 R935189 R935190 R935191 0.068 0.043 0.213 0.0710.027 R935192 R935193 0.08 0.048 0.312 0.092 0.037 R935194 0.125 0.0540.493 0.118 0.034 R935196 R935197 R935198 R935199 R935202 R935203R935204 R935205 R935206 R935207 R935208 R935209 R935211 R935212 R935213R935214 R935218 R935219 R935220 R940089 R940090 R940095 R940100 R940215R940216 R940217 R940222 R940233 R940235 R940250 R940251 R940253 R940254R940255 R940256 R940257 R940258 R940260 R940261 R940262 R940263 R940264R940265 0.981 0.306 1.211 1.131 0.486 R940266 R940267 R940269 R940270R940271 R940275 R940276 0.136 0.073 0.332 0.251 <0.056 R940277 0.2790.315 0.625 0.262 0.181 R940280 R940281 R940282 R940283 R940284 R940285R940286 R940287 R940288 R940289 R940290 0.255 0.545 0.59 0.246 0.1R940291 R940292 R940293 R940294 R940295 R940296 R940297 R945025 R945032R945033 R945034 R945035 R945036 R945037 R945038 R945040 R945041 R945042R945043 R945045 R945046 R945047 R945048 R945051 R945052 R945053 R945056R945057 R945060 R945061 R945062 R945063 R945064 R945065 R945066 R945067R945068 R945070 R945071 R945096 R945097 R945109 R945110 R945117 R945118R945124 R945125 R945126 R945127 R945128 R945129 R945130 R945131 R945132R945133 R945134 R945135 R945137 R945138 R945139 R945140 R945142 R945144R945145 R945146 R945147 R945148 R945149 R945150 >2 >2 9999 0.709 0.634R945151 R945152 R945153 R945155 R945156 R945157 R945162 R945163 R945164R945165 R945166 R945167 R945168 R945169 R945170 R945171 R945172 R945173R945175 R950082 R950083 R950090 R921302 0.282 R950092 R950093 R950100R950107 R950108 R950109 R950120 R950121 R950122 R950123 R950125 R950129R950130 R950131 R950132 R950133 R950134 R950135 R950137 R950138 R950139R950140 R950141 R950142 R950143 R950144 R950145 R950146 R950147 R950148R950149 R950150 R950151 R950152 R950153 R950154 R950155 R950156 R950157R950158 R950159 R950160 R950162 R950163 R950164 R950165 R950166 R950167R950168 R950169 R950170 R950171 R950172 R950173 R950174 R950175 R950176R950177 R950178 R950179 R950180 R950181 R950182 R950183 R950184 R950185R950186 R950187 R950188 R950189 R950190 R950191 <0.22 >2 0.401 <0.22<0.22 R950192 R950193 R950194 R950195 R950196 R950197 R950198 R950199R950200 R950201 R950202 R950203 R950204 R950205 R950206 R950207 <0.22<0.22 0.288 <0.22 <0.22 R950208 R950209 R950210 R950211 R950212 R950213R950214 R950215 R950216 R950217 R950218 R950219 R950220 R950221 R950222R950223 R950224 R950225 R950226 R950227 R950229 R950230 R950231 R950232R950233 R950234 R950235 R950236 R950237 R950238 R950239 R950240 R950241R950251 R950253 R950254 R950255 R908698 R908699 R908700 R908701 R908702R908703 R908704 R908705 R908706 R908707 R908709 R908710 R908711 R908712R908734 R909255 R909259 R909260 R909261 R909263 R909264 R909265 R909266R909267 R909268 R909290 R909292 R909308 R909309 R920394 R920395 R920396R920397 R920398 R920399 R920404 R920405 R920406 R920407 R920408 R920410R920411 R925745 R926238 R926752 R926753 R926754 R926755 R926756 R926757R926759 R926760 R926761 R926762 R926763 R926794 R926826 R926827 R926828R926829 R926830 R926831 R926832 R926833 R926834 R926835 R926836 R926837R926838 R926839 R926840 R926841 R926842 R926843 R926844 R926845 R926846R926847 R926848 R926851 R926855 R926856 R926857 R926859 R926860 R926862R926863 R926866 R926870 R926871 R926874 R926879 R926880 R926881 R926883R926885 R926886 R926887 R926890 R926891 R926892 R926893 R926894 R926895R926896 R926897 R926898 R926899 R926900 R926902 R926903 R926904 R926905R926906 R926907 R926908 R926909 R926913 R926914 R926915 R926916 R926917R926918 R926919 R926922 R926923 R926925 R926926 R926927 R926928 R926929R926930 R926931 R926932 R926933 R926934 R926935 R926936 R926937 R926938R926939 R926940 R926941 R926942 R926943 R926944 R926945 R926946 R926947R926948 R926949 R926950 R926951 R926953 R926954 R926955 R926956 R927016R927017 R927018 R927019 R927020 R927023 R935221 R935222 R935223 R935224R935225 R935237 R935238 R935239 R935240 R935242 R935248 R935249 R935250R935251 R935252 R935253 R935255 R935256 R935258 R935259 R935261 R935262R935263 R935264 R935266 R935267 R935268 R935269 R935271 R935276 R935277R935278 R935279 R935280 R935281 R935286 R935287 R935288 R935289 R935290R935291 R935292 R935293 R935294 R935295 R935296 R935297 R935298 R935299R935300 R935301 R935302 R935303 R935304 R935305 R935306 R935307 R935308R935309 R935310 R935320 R935321 R935322 R935323 R935324 R935336 R935337R935338 R935339 R935340 R935351 R935352 R935353 R935354 R935355 R935356R935357 R935358 R935359 R935360 R935361 R935362 R935363 R935364 R935365R935366 R935367 R940079 R940110 R940299 R940300 R940301 R940304 R940306R940307 R940308 R940309 R940311 R940312 R940314 R940316 R940317 R940318R940319 R940321 R940323 R940337 R940338 R921303 R940345 R940346 R940347R940348 R940349 R940350 R940351 R940352 R940353 R940354 R945236 R945237R945242 R945263 R921304 R945299 R950244 R950245 R950246 R950247 R950261R950262 R950263 R950264 R950265 R950266 R950267 R950290 R950291 R950293R950294 R950295 R950296 R950344 R950345 R950346 R950347 R950348 R950349R950356 R950368 R950371 R950372 R950373 R950374 R950376 R950377 R950378R950379 R950380 R950381 R950382 R950383 R950385 R950386 R950388 R950389R950391 R950392 R950393 R945028 R935241 R940298 R940302 R940303 R940305R935260 R909258 R940313 R940315 R935275 R940320 R940322 R926910 R926911R926912 R926853 R926852 R926854 R926920 R926921 R926924 R926858 R926861R945298 R940328 R926869 R926873 R926875 R926876 R926877 R940336 R926878R926882 R926884 R926889 R920400 R920401 R920402 R920403 R940342 R920409R940344 R926888 R926758 R927024 R927025 R927026 R927027 R927028 R927029R927030 R927031 R927032 R927035 R927036 R927037 R927038 R927039 R927040R927041 R927042 R935270 R935368 R935369 R935370 R935371 R935372 R935373R935374 R935375 R935376 R935377 R935378 R935379 R935380

TABLE 2 High Density CHMC Toxicity high CHMC CHMC CHMC CHMC CHMCToxicity Toxicity Toxicity BJAB density high density high density highdensity high density high density Jurkat Jurkat BJAB Cell hexos tryptasehistamine LTC4 TNF-alpha IL-13 Light Scat. Cell Titer Glo Light Scat.Titer Glo R008951 R008952 R008953 R008955 R008956 R008958 R067934R067963 R070153 R070791 R081166 R088814 R088815 R091880 R092788 99999999 R909241 3.736 R921219 0.124 0.121 0.162 0.034 0.190 0.175 >10 >10R925775 9999 9999 R925778 9999 9999 R925779 >10 9999 R925797 >10 9999R926108 >10 >10 R926109 0.783 0.906 1.827 0.808 1.504 1.664 >10 9999R926110 >10 >10 R921218 0.464 0.647 0.463 0.695 1.752 2.0776 >10 >10R926113 1.448 1.649 1.848 0.468 5.678 3.569 >10 >10 R926146 9999 9999R926210 >10 9999 R926240 10 9999 R926248 >10 9999 R926249 >10 9999R926253 9999 9999 R926256 >10 9999 R926258 9999 9999 R926387 >10 9999R926395 >10 9999 R926396 >10 9999 R926411 8.5 >10 R926486 1.088 1.3131.928 0.834 0.455 R926488 0.521 0.623 0.792 0.201 2.443 1.012 R9264930.889 1.093 1.324 0.474 >2 >4.33 R926494 0.640 >2 9999 0.326 9999R926495 0.100 0.235 0.066 0.241 0.362 0.449 >10 >10 R926496 0.429 0.5330.809 0.414 0.622 R926497 1.106 1.234 1.333 1.876 9999 R926501 >2 >29999 9999 9999 >4.33 >4.33 R926502 >2 >2 >2 1.807 >2 1.513 R926505 4.199R926508 0.170 0.434 0.105 0.505 0.763 >10 >10 R926510 0.921 1.115 1.6670.417 0.686 2.77 R926511 1.183 1.474 1.73 1.307 >2 >4.33 >4.33R926614 >10 >10 >10 6.442 R926696 <1.1 <1.1 <1.1 <1.1 <1.1 1.773 >5.0R926699 <1.1 <1.1 1.44 <1.1 <1.1 1.294 R926700 <1.1 <1.1 <1.1 <1.1 <1.12.053 R926703 1.512 1.947 >2 0.724 >2 R926704 >2 9999 9999 9999 9999R926705 1.007 1.256 0.641 0.494 9999 R926706 >2 9999 9999 1.491 9999R926742 0.104 0.217 0.080 0.385 0.667 9 >10 R926745 >10 >10 R926780 >5.0R926782 >4.33 >4.33 R935075 0.647 1.212 0.443 <0.22 >2 >4.33 >4.33R935154 >4.33 R935156 4.054 R940216 <1.1 <1.1 1.176 <1.1 3.188 3.006R940233 0.577 0.642 0.586 0.118 2.247 1.781 >4.33 >4.33 R945032 0.3570.458 0.439 0.0929 1.082 0.291 R945033 8.151 8.868 >10 5.983 R945071<1.1 <1.1 <1.1 <1.1 <1.1 <1.1 R945128 1.279 1.749 0.547 0.729 >2 NDR945140 0.994 1.112 1.551 1.714 9999 R945142 >2 >2 9999 >2 9999R945150 >4.33 >4.33 R921302 0.682 0.795 1.588 0.514 1.173 1.672 R9501410.567 0.618 0.627 0.201 1.059 0.798 R950207 >4.33

7.7 The 2,4-Pyrimidinediamine Compounds of the Invention SelectivelyInhibit the Upstream IgE Receptor Cascade

To confirm that many of the 2,4-pyrimidinediamine compounds of theinvention exert their inhibitory activity by blocking or inhibiting theearly IgE receptor signal transduction cascade, several of the compoundswere tested in cellular assays for ionomycin-induced degranulation, asdescribed below.

7.7.1 CHMC Low Cell Density Ionomycin Activation: Tryptase Assay

Assays for ionomycin-induced mast cell degranulation were carried out asdescribed for the CHMC Low Density IgE Activation assays (Section 6.4.3,supra), with the exception that during the 1 hour incubation, 6×ionomycin solution [5 mM ionomycin (Signma I-0634) in MeOH (stock)diluted 1:416.7 in MT buffer (2 μM final)] was prepared and cells werestimulated by adding 25 μl of the 6× ionomycin solution to theappropriate plates.

7.7.2 Basophil Ionomycin Activation: Histamine Release Assay

Assays for ionomycin-induced basophil cell degranulation were carriedout as described for the Basophil IgE or Dustmite Activation Assay(Section 6.4.6, supra), with the exception that following incubationwith compound, cells were stimulated with 20 μl of 2 μM ionomycin.

7.7.3 Results

The results of the ionomycin-induced degranulation assays, reported asIC₅₀ values (in μM) are provided in TABLE 1, supra. Of the activecompounds tested (i.e., those that inhibit IgE-induced degranulation),the vast majority do not inhibit ionomycin-induced degranulation,confirming that these active compounds selectively inhibit the early (orupstream) IgE receptor signal transduction cascade.

These results were confirmed for certain compounds by measuringanti-IgE-induced and ionomycin-induced calcium ion flux in CHMC cells.In these Ca²⁺ flux tests, 10 μM R921218 and 10 μM R902420 inhibitedanti-IgE-induced Ca²⁺ flux, but had no effect on ionomycin-induced Ca²⁺flux (See FIG. 4).

7.8 The Inhibitory Effect of the 2,4-Pyrimidinediamine Compounds of theInvention is Immediate

To test the immediacy of their inhibitory effect, certain2,4-pyrimidinediamines of the invention were added simultaneously withanti-IgE antibody activator in the cellular assays described above. Allcompounds tested blocked IgE-induced degranulation of CHMC cells to thesame extent as observed when the compounds were pre-incubated with CHMCcells for 10 or 30 min. prior to receptor cross-linking.

7.9 Kinetics of Pharmacological Activity In Vitro

Compounds R921218, R921302, R921219, R926240, R940277, R926742, R926495,R909243 and R926782 were tested in washout experiments. In theexperiments, CHMC cells were either activated immediately with anti-IgEantibody in the presence of 1.25 μM compound (time zero), or thecompound was washed out followed by activation with anti-IgE antibody at30, 60 or 120 min. The inhibitory activity of these compounds wasgreatly diminished 30 min. after compound removal, indicating thatconstant exposure of mast cells to these compounds is required formaximal inhibition of degranulation The other compounds tested yieldedsimilar results.

7.10 Toxicity: T- and B-Cells

The ability of the compounds of the invention to exert their inhibitoryactivity without being toxic to cells of the immune system wasdemonstrated in cellular assays with B- and T-cells. The protocols forthe assays are provided below.

7.10.1 Jurkat (T-Cell) Toxicity

Dilute Jurkat cells to 2×10⁵ cells/ml in complete RPMI (10%heat-inactivated fetal bovine serum) media and incubate at 37° C., 5%CO₂ for 18 hours. Add 65 ul cells at 7.7×10⁵ cells/ml to a 96-wellV-bottom plate (TC-treated, Costar) containing 65 ul 2× compound (finalvehicle concentration is 0.5% DMSO, 1.5% MeOH). Mix, incubate plates for18-24 hr at 37° C., 5% CO₂. Toxicity was assessed by flow cytometricanalysis of cellular light scatter

7.10.2 BJAB (B-Cell) Toxicity

The B-cell line BJAB was cultured in log phase in RPMI1640+10%heat-inactivated fetal bovine serum, 1× L-glutamine, 1× penicillin, 1×streptavidin and 1× beta-mercaptoethanol at 37° C., 5% CO₂. First, BJABswere harvested, spun and resuspended in culture medium to aconcentration of 7.7×10⁵ cells/mL. 65 uL cells were mixed with 65 uLcompound, in duplicate and in the presence of 0.1% DMSO in a V-bottomed96-well tissue culture plate. Cells were incubated with compound atvarious dilutions at 37° C., 5% CO₂. Toxicity was assessed by flowcytometric analysis of cellular light scatter.

7.10.3 Toxicity: Cell Titer Glo Assay

Seed 50 μl cells (1×10⁶/ml) into each well containing 50 μl compound.The final vehicle concentration is 0.5% DMSO, 1.5% MeOH. Shake platesfor 1 minute to mix cells and compound. Incubate plates at 37° C. (5%CO₂) for 18 hours. Next day, harvest 50 μl cells from each well, add to50 μl Cell Titer Glo reagent (Invitrogen). Shake plates for 1 minute.Read on luminometer.

7.10.4 Results

The results of the T- and B-cell toxicity assays, reported as IC50values (in μM), are presented in TABLE 2, supra. With a few exceptions(see TABLE 1), all compounds tested were non-toxic to both B- andT-cells at effective inhibitory concentrations. Assays performed withprimary B-cells yielded similar results.

7.11 The 2,4-Pyrimidine Compounds are Tolerated in Animals

The ability of the compounds of the invention to exert their inhibitoryactivity at doeses below those exhibiting toxicity in animals wasdemonstrated with compounds R921218, R921219 and R921302.

7.11.1 R921218

R921218 was studied in an extensive program of non-clinical safetystudies that concluded this agent to be well tolerated in both rodentsand non-rodents. To summarize the outcome of toxicology/non-clinicalsafety testing with R921218; this agent produced no dose limitingtoxicity by the intranasal route of administration in non-rodents(rabbits and primates) or by the oral route of administration in rodents(mice and rats) during 14-day repeat-dose toxicity studies at doses manyfold above the anticipated dose expected to produce efficacy in man.There were no adverse findings in a core safety pharmacology battery ofcardiovascular, respiratory and/or central nervous system function.There was no evidence for mutagenic or clastogenic potential in genetictoxicology testing nor were there untoward effects after exposure toskin and eyes. A short discussion of key toxicology studies is provided.

A 14-day repeat-dose intranasal toxicity study in Cynomolgus monkeys wasperformed at doses of 2.1, 4.5 or 6.3 mg/kg/day. In life parametersincluded: clinical observations, body weights, food consumption,ophthalmology, blood pressure, electrocardiography, hematology, clinicalchemistry, urinalysis, immunotoxicological assessment, gross necropsy,organ weights, toxicokinetic assessments and histopathology (includingthe nasal cavity). There were no adverse findings attributed to R921218in any study parameter and the NOAEL (no observed adverse effect level)was considered 6.3 mg/kg/day.

A 14-day repeat-dose intranasal toxicity study in New Zealand Whiterabbits was performed at doses of 1.7, 3.4 or 5.0 mg/kg/day. In lifeparameters included: clinical observations, body weights, foodconsumption, ophthalmology, hematology, clinical chemistry, grossnecropsy, organ weights, toxicokinetic assessments and histopathology(including the nasal cavity). There were no adverse findings attributedto R921218 in any study parameter and the NOAEL (no observed adverseeffect level) was considered 5.0 mg/kg/day.

7.11.2 R921219

In pilot dose finding studies a single dose oral dose of 600 mg/kg wasconsidered a NOEL (no observed effect level) while multiple (7-day)doses of 200 mg/kg/day and above were not tolerated.

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921219 was found to test positive in testerstrain TA1537, with and without metabolic activation, confirming theresults of an earlier study. R921219 was not found to adversely affectany of the other 4 tester strains. R921219 was not found to possessclastogenic potential when studied in an in vitro chromosomal aberrationassay.

7.11.3 R921302

Several non-GLP pilot toxicity studies have been conducted in rodents.In the mouse an oral dose of 1000 mg/kg was tolerated for up to 7-days.In a 14-day oral toxicity study in the mouse was conducted with doses of100, 300 and 1000 mg/kg. A dose of 1000 mg/kg was not tolerated, while adose of 300 mg/kg promoted evidence for histopathological changes in thevulva. A dose of 100 mg/kg was considered the NOAEL (no observed adverseeffect level) in the study. A 28-day oral toxicity study in the mousewas conducted at doses of 100 mg/kg q.d., 100 mg/kg b.i.d., 300 mg/kgq.d. and 300 mg/kg b.i.d. R921302 was not tolerated at 300 mg/kg q.d. orb.i.d. The lower doses (100 mg/kg q.d. or b.i.d.) appeared to be welltolerated (results of clinical and histopathology are not yet known). Inthe rat oral doses of 50, 150 and 300 mg/kg given for 32 days appearedto be well tolerated (results of clinical and histopathology are not yetknown).

In the in vitro Salmonella-Escherichia coli/Mammalian-Microsome ReverseMutation Assay (Ames test), R921302 was found to test positive in testerstrain TA98 with S9 and TA1537, with and without metabolic activation.R921302 was not found to adversely affect any of the other 3 testerstrains. R921302 was not clastogenic when assessed in an in vitrochromosomal aberration assay.

7.12 The 2,4-Pyrimidinediamine Compounds are Orally Bioavailable

Over 50 2,4-pyrimidinediamine compounds of the invention were tested fororal bioavailability. For the study, compounds were dissolved in variousvehicles (e.g. PEG 400 solution and CMC suspension) for intravenous andoral dosing in the rats. Following administration of the drug, plasmasamples were obtained and extracted. The plasma concentrations of thecompounds were determined by high performance liquidchromatography/tandem mass spectrometry (LC/MS/MS) methods.Pharmacokinetic analyses were performed based on the plasmaconcentration data. The pharmacokinetic parameters of interest includeClearance (CL), Volume of distribution at steady-state (Vss), terminalhalf-life (t_(1/2)), and oral bioavailability (% F).

These pharmacokinetic studies indicate that many of the2,4-pyrimidinediamine compounds are orally available, with % F up toapproximately 50% (in the range of 0-50%). The half-lives ranged from0.5 to 3 hr. In particular, Compounds R940350, R935372, R935193, R927050and R935391 exhibited good oral bioavailabilities and half-lives inrats. Thus, these studies confirm that these 2,4-pyrimidinediaminecompounds are suitable for oral administration.

7.13 The Compounds are Effective for the Treatment of Allergies

The in vivo efficacy of compounds R926109, R921218, R921219, R921302,R926495, R926508, R926742, R926745 and R945150 towards allergies wasevaluated in the mouse model of passive cutaneous anaphylaxis (PCA).This model provides a direct measure of IgE-induced degranulation oftissue mast cells. In this model, IgE primed animals are exposed to anallergen challenge, and the change in permeability of dermal vasculaturethat results from histamine release from mast cells is measured bychange in the amount of dye leakage into surrounding tissue. Inhibitionof mediator release by compounds that modulate mast cell degranulationis easily measured by extracting the dye from the tissue.

7.13.1 Study Protocol and Results

In the PCA assay mice are passively sensitized by intradermal injectionwith anti-dinitrophenol (DNP) IgE antibodies (Day-1). At predeterminedtimes animals are treated with the test agent (Day 0). The modulatoryeffect of the agent on cutaneous mast cell degranulation is measuredfollowing intravenous injection of DNP conjugated to human serum albumin(HSA-DNP), together with Evans blue dye. The resulting cross-linking ofthe IgE receptor and subsequent mast cell degranulation-induced increasein vascular permeability is determined by measuring the amount of dyeextravasation into the tissue. Dye is extracted from the tissue byformamide, and the absorbance of this extract is read at 620 nm. Theinhibitory effect of drug treatment is reported as the percentinhibition compared to vehicle treatment, that is, the percent reductionin A₆₂₀.

Two compounds have been tested as positive controls: the histamineantagonist diphenhydramine and the serotonin antagonist cyproheptadine.Both mediators (histamine and serotonin) are released upon IgE-mediateddegranulation from the mouse mast cell. Both reference compounds inhibitthe PCA response; cyproheptadine was used routinely in subsequentexperiements. Cyproheptadine reproducibly inhibited the PCA response by61%+/−4% (8 mg/kg, i.p., 30 minutes pretreatment time, n=23experiments).

7.13.1.1 Results

A dose-dependent inhibition of the FcεR-mediated vascular leakage wasobserved with increasing doses of R921218, R926109, R921219 andRR921302. These compounds were administered either in a solutionformulation (67% PEG/33% citrate buffer) or an aqueous suspension (1.5%Avicel). These results demonstrate the strong correlation betweencompound plasma levels, in vivo efficacy, and in vitro potency. The mostpotent compound, R921219, was active with circulating exposure levels ofapproximately 10 μg/ml (68% inhibition at a dose level of 100 mg/kg)compared with R921302, a relatively less potent molecule, which reducedplasma extravasation by 42% at a dose level of 100 mg/kg. Further, thelength of exposure to circulating compound was reflected in the durationof inhibitory activity. R921302, determined to be the most metabolicallystable compound in pharmacokinetics studie, inhibited the vascularpermeability for 1-2 hours prior to antigen-induced receptor signaling,where after the efficacy began to decrease. These data are summarized inTABLE 3 and TABLE 4.

TABLE 3 Efficacy of R921218, R926109, R921219 and R921302 in the PCAAssay Pretreat- Plasma Com- ment Dose % Inhi- level pound Route Vehicletime (min) (mg/kg) bition (μg/ml) R921218 PO 67% PEG/ 10 50 7 3 33% 10011 4 citrate buffer 200 50 18 R926109 PO 67% PEG/ 15 50 22 N.D. 33% 10032 citrate buffer 200 48 R921219 PO 1.5% 15 30 25 0.4 Avicel/water 10068 4 300 92 11 R921302 PO 1.5% 60 50 35 25 Avicel/water 100 42 38 150 5664 200 93 105

TABLE 4 Duration of action of R921219 and R921302 in the PCA AssayPlasma Com- Dose Pretreatment % level pound Route Vehicle (mg/kg) time(min) Inhibition (μg/ml) RR921302 PO 1.5% 200 30 89 88 Avicel/ 60 83 53water 120 82 61 240 37 8Similar in vivo activity was observed with compounds R926495, R926508,R926742, R926745 and R9261550, which were able to inhibit the PCAresponse after administration by the oral route in a PEG-basedformulation (data not shown).

7.14 The Compounds are Effective in the Treatment of Asthma

The efficacy of compounds R921218, R921302, R926495, R926508, R926742and R921219 in the treatment of asthma was demonstrated in the sheepmodel of allergic asthma. Sheep develop bronchoconstriction withinminutes of exposure to inhaled antigen (Ascaris suum), with maximalairflow obstruction during the early allergic response (EAR). Release ofpreformed mast cell mediators is likely responsible for this early phaseof airflow obstruction. In addition to the EAR, the sheep model allowsus to evaluate the effect of our compounds on the late asthmaticreaction (LAR) and non-specific airway hyperresponsiveness (AHR), whichoccur as a result of topical or local administration of allergen to theairway. In the sheep, AHR develops a few hours following antigenchallenge, and can persist for up to 2 weeks. The results describedbelow demonstrate the potential of the tested compounds to inhibit acascade of events that may be a result of release of cytokines from themast cell.

7.14.1 Study Protocol

In the sheep model of allergic asthma, sheep are administered aerosolsof test article via an endotracheal tube, followed by an aerosolchallenge with antigen extracted from the roundworm, Ascaris suum, towhich the sheep are naturally allergic. Allergen challenge leads todirect bronchoconstriction (both EAR and LAR) and a persistentnon-specific AHR. These three characteristics are similar to those seenin human allergic asthmatics. The activity of the test agent isdetermined by changes in the lung resistance (R_(L)), which iscalculated from measurements of transpulmonary pressure, flow, andrespiratory volume. The historical control data obtained from the samesheep following saline treatment compared with an allergen challengeshow that a sharp increase of R_(L) occurs during the EAR and persistsfor approximately 2-3 hours following allergen challenge. The LAR is aless pronounced increase in R_(L), which starts approximately 5-6 hoursfollowing allergen challenge and is resolved by 8 hours post-challenge.Twenty-four hours after the challenge, a dose response to carbachol ismeasured to determine the AHR, which is expressed as the dose ofcarbachol required to increase R_(L) by 400% over baseline. (Thismeasurement is referred to as the provocative concentration of carbacholthat elicits a 400% increase in RL over baseline (PC₄₀₀). The data arecompared to historical control data for the same individual whenadministered a saline control aerosol and challenged with Ascaris suum.

7.14.2 Result

All the compounds tested showed inhibitory effects in the LAR and theAHR, and several of these agents inhibited the EAR as well. The optimalresponse for each compound in a series of studies to evaluate activityat several pretreatment times and using several different solution andsuspension formulations are shown in TABLE 5. The efficacy of R921218 onthe EAR appeared to be dependent on the formulation, with the greatesteffect seen at 30 mg/sheep administered as a solution aerosol in 10%ethanol. R926495, R926742, R926508 and R921219, administered in fourdifferent sheep at 45 mg/sheep in an aqueous suspension 60 minutes priorto allergen challenge, demonstrate that the LAR and AHR is blocked. Inaddition to these late parameters, the EAR was greatly reduced bytreatment with R921219, R926508 or R926495. The efficacy of RR921302 wasinvestigated using a 45% PEG400/55% citrate buffer vehicle. Under theseconditions, R921302, administered at 30 mg/sheep 60 minutes prior tochallenge, blocked the LAR and AHR, and EAR was unaffected.

These data clearly demonstrate that these compounds are able to blockthe asthmatic responses in allergic sheep. All compounds inhibited theAHR and LAR significantly when compared to the historical control. TheEAR was significantly inhibited by R921219, R926508 and R926495 (54%,21% and 33% respectively). In contrast, R921218, R921302 and R926742failed to inhibit the EAR when administered in an aqueous suspension.

TABLE 5 Efficacy Of Exemplary Compounds In A Sheep Model Of AllergicAsthma Dose Pretreatment EAR (% LAR (% AHR (% Compound (mg/sheep) time(min) Vehicle inhibition) inhibition) inhibition) R921218 30 15 10%ethanol 66 78 101 R926742 45 60 Aqueous suspension −19 87 94 R926495 4560 33 85 41 R926508 45 60 21 90 88 R921219 45 60 56 75 90 RR921302 30 6045% PEG400/55% −28 86 82 citrate buffer

7.15 The Compounds are Effective in the Treatment of Asthma

The efficacy of compounds R921304 and R921219 in the treatment of asthmawas also demonstrated in a mouse model of allergic asthma.

7.15.1 Study Protocol

Mice are sensitized to ovalbumin (chicken protein) in the presence of anadjuvant (Alum) by the intraperitoneal route on day 0 and day 7. Oneweek later, mice are challenged intranasally with ovalbumin on Days 14,15 and 16 (more stringent model) or on Day 14 (less stringent model).This sensitization and challenge regimen leads to airwayhyperresponsiveness and inflammation in the lungs, which are twodominant characteristics of human allergic asthma. In the mouse model,the in vivo airway responses are measured using a whole bodyplethysmograph which determines the PENH (enhanced Pause, BuxcoElectronics). The PENH is a dimensionless value comprised of the peakinspiratory flow (PIF), peak expiratory flow (PEF), time of inspiration,time of expiration and relaxation time, and is considered a validatedparameter of airway responsiveness. Responses to allergen challenge(OVA) are compared with animals challenged with saline only. Twenty-fourhours after challenge, mice are exposed to increasing doses ofmethacholine (muscarinic receptor agonist) which results in smoothmuscle contraction. The ovalbumin-challenged mice demonstrate asignificant airway hyperresponsiveness to methacholine when compared tothe saline challenged mice. In addition, a cellular infiltrate in theairway is observed in ovalbumin challenged mice when compared with thesaline challenged mice. This cellular infiltrate is mainly characterizedby eosinophils, but a smaller influx of neutrophils and mononuclearcells is also present.

The use of this model for the evaluation of small molecule inhibitors ofmast cell degranulation has been validated is several ways. First, usingmast cell deficient mice (W/W^(v)) it has been shown that theovalbumin-induced responses are dependent upon the presence of mastcells. In the mast cell deficient mice, ovalbumin sensitization andchallenge did not result in airway hyperresponsiveness and eosinophilinflux. Second, the mast cell stabilizer, Cromolyn, was able to blockthe ovalbumin-induced airway hyperresponsiveness and inflammation (datanot shown). The use of this model to evaluate compounds for thetreatment of asthmatic responses that may be mediated by mechanismsother than mast cell stablization, is further supported by theinhibitory effect of the steroids, dexamethasone and budesonide, onmethacoline-induced bronchocontriction.

7.15.2 Results

The efficacy of R921304 was evaluated by intranasal administration on 10consecutive days, from Day 7 through Day 16, at a dose level of 20mg/kg, with the last 3 doses administered 30 minutes prior to eithersaline or ovalbumin challenge. R⁹²¹³⁰⁴ was able to inhibit theovalbumin-induced airway hyperresponsiveness to methacholine whencompared to the vehicle treated mice.

In a less stringent protocol, in which the mice were challenged withovalbumin only once on Day 14, R921219 administered subcutaneously at 70mg/kg in 67% PEG400/33% citrate buffer 30 minutes prior to saline orovalbumin challenge, demonstrates that R921219 completely blocked theovalbumin-induced airway hyperresponsiveness and cellular influx.

These results clearly demonstrate that R921219 and R921304 areefficacious in inhibiting the airway responses in a mouse model ofallergic asthma.

7.16 2,4-Pyrimidinediamine Compounds Inhibit Phosphorylation of ProteinsDownstream of Syk kinase in Activated Mast Cells

The inhibitory effect of the 2,4-pyrimidinediamine compounds on thephosphorylation of proteins downstream of Syk kinase was tested withcompounds R921218, R218219 and R921304 in IgE receptor-activiated BMMCcells.

For the assay, BMMC cells were incubated in the presence of varyingconcentrations of test compound (0.08 μM, 0.4 μM, 2 μM and 10 μM) for 1hr at 37° C. The cells were then stimulated with anti-IgE antibody aspreviously described. After 10 min, the cells were lysed and thecellular proteins separated by electrophoresis (SDS PAGE).

Following electrophoresis, the phosphorylation of the proteins indicatedin FIGS. 7, 10 and 11A-D were assessed by immunoblot. Antibodies werepurchased from Cell Signaling Technology, Beverley, Mass.

Referring to FIGS. 7, 10 and 11A-D, the indicated compounds testedinhibited phosphorylation of proteins downstream of Syk, but notupstream of Syk, in the IgE receptor signaling cascade, confirming boththat the compounds inhibit upstream IgE induced degranulation, and thatthe compounds exhert their inhibitory activity by inhibiting Syk kinase.

7.17 2,4-Pyrimidinediamine Compounds Inhibit Syk Kinase in BiochemicalAssays

Several 2,4-pyrimidinediamine compounds were tested for the ability toinhibit Syk kinase catalyzed phosphorylation of a peptide substrate in abiochemical fluorescenced polarization assay with isolated Syk kinase.In this experiment, Compounds were diluted to 1% DMSO in kinase buffer(20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2 mM MnCl₂, 1 mM DTT, 0.1 mg/mLacetylated Bovine Gamma Globulin). Compound in 1% DMSO (0.2% DMSO final)was mixed with ATP/substrate solution at room temperature. Syk kinase(Upstate, Lake Placid N.Y.) was added to a final reaction volume of 20uL, and the reaction was incubated for 30 minutes at room temperature.Final enzyme reaction conditions were 20 mM HEPES, pH 7.4, 5 mM MgCl₂, 2mM MnCl₂, 1 mM DTT, 0.1 mg/mL acetylated Bovine Gamma Globulin, 0.125 ngSyk, 4 uM ATP, 2.5 uM peptide substrate (biotin-EQEDEPEGDYEEVLE-CONH2,SynPep Corporation). EDTA (10 mM final)/anti-phosphotyrosine antibody(1× final)/fluorescent phosphopeptide tracer (0.5× final) was added inFP Dilution Buffer to stop the reaction for a total volume of 40 uLaccording to manufacturer's instructions (PanVera Corporation) The platewas incubated for 30 minutes in the dark at room temperature. Plateswere read on a Polarion fluorescence polarization plate reader (Tecan).Data were converted to amount of phosphopeptide present using acalibration curve generated by competition with the phosphopeptidecompetitor provided in the Tyrosine Kinase Assay Kit, Green (PanVeraCorporation).

The results of the assay are shown in TABLE 6, below:

TABLE 6 Compound No. IC50 (in μM) R926505 0.0703 R926508 0.1315 R9265940.7705 R926715 0.534 R926745 0.0925 R926782 0.1165 R926791 0.207 R9268130.4047 R926816 0.0615 R935138 0.2288 R935190 0.0465 R935191 0.045R935193 0.075 R935194 0.1687 R935196 0.2655 R940255 0.7705 R940256 2.787R940269 0.685 R940275 0.7335 R940276 0.1265 R940277 0.2143 R940290 0.187R945071 0.4295 R945140 0.611 R945142 2.007 R945144 0.383 R921302 0.2678R908702 0.0378 R908712 0.024 R909268 0.1253 R920410 0.157 R926753 0.108R926757 0.5103 R926834 0.292 R926839 0.055 R926891 0.1695 R926931 0.2553R935237 0.0455 R935293 0.0465 R935302 0.0265 R935304 0.042 R935307 0.057R935309 0.098 R935310 0.2003 R940323 0.062 R940338 0.028 R921303 0.00045R940347 0.0345 R921304 0.01275 R950368 0.0107 R950373 0.0665

These data demonstrate that all of the compounds tested, except forR945142 and R909236 inhibit Syk kinase phosphorylation with IC₅₀s in thesubmicromolar range. All compounds tested inhibit Syk kinasephosphorylation with IC₅₀s in the micromolar range.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

All literature and patent references cited throughout the applicationare incorporated by reference into the application for all purposes.

1.N4-[2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediamineor a salt, hydrate, solvate and/or N-oxide thereof.
 2. A pharmaceuticalcomposition comprising aN4-[2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminecompound or a pharmaceutically acceptable salt, hydrate, solvate and/orN-oxide thereof and a pharmaceutically acceptable carrier, diluentand/or excipient.
 3. The composition of claim 2 in which theN4-[2,2-difluoro-4H-benzo[1,4]oxazin-3-one)-6-yl]-5-fluoro-N2-[3-(methylaminocarbonylmethyleneoxy)phenyl]-2,4-pyrimidinediaminecompound is in the form of a pharmaceutically acceptable salt, ahydrate, a solvate and/or an N-oxide.
 4. The composition of claim 2 inwhich the pharmaceutically acceptable salt is a hydrochloride salt, ahydrogen sulfate salt, a sulfate salt, a phosphate salt, an alkanesulfonate salt, a methane sulfonate salt, an ethane sulfonate salt, ahydroxynaphthoate salt or a p-toluene sulfonate salt.